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Annex I Summary of Product Characteristics
Annex I Summary of Product Characteristics
1
This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
See section 4.8 for how to report adverse reactions.
3. PHARMACEUTICAL FORM
4. CLINICAL PARTICULARS
Xarelto, co-administered with acetylsalicylic acid (ASA) alone or with ASA plus clopidogrel or
ticlopidine, is indicated for the prevention of atherothrombotic events in adult patients after an acute
coronary syndrome (ACS) with elevated cardiac biomarkers (see sections 4.3, 4.4 and 5.1).
Posology
The recommended dose is 2.5 mg twice daily.
Patients should also take a daily dose of 75 - 100 mg ASA or a daily dose of 75 - 100 mg ASA in
addition to either a daily dose of 75 mg clopidogrel or a standard daily dose of ticlopidine.
Treatment should be regularly evaluated in the individual patient weighing the risk for ischaemic
events against the bleeding risks. Extension of treatment beyond 12 months should be done on an
individual patient basis as experience up to 24 months is limited (see section 5.1).
Treatment with Xarelto should be started as soon as possible after stabilisation of the ACS event
(including revascularisation procedures); at the earliest 24 hours after admission to hospital and at the
time when parenteral anticoagulation therapy would normally be discontinued.
If a dose is missed the patient should continue with the regular dose as recommended at the next
scheduled time. The dose should not be doubled to make up for a missed dose.
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Converting from Vitamin K Antagonists (VKA) to Xarelto
When converting patients from VKAs to Xarelto, International Normalized Ratio (INR) values will be
falsely elevated after the intake of Xarelto. The INR is not valid to measure the anticoagulant activity
of Xarelto, and therefore should not be used (see section 4.5).
Special populations
Renal impairment
Limited clinical data for patients with severe renal impairment (creatinine clearance 15 - 29 ml/min)
indicate that rivaroxaban plasma concentrations are significantly increased. Therefore, Xarelto is to be
used with caution in these patients. Use is not recommended in patients with creatinine clearance
< 15 ml/min (see sections 4.4 and 5.2).
No dose adjustment is necessary in patients with mild renal impairment (creatinine clearance
50 - 80 ml/min) or moderate renal impairment (creatinine clearance 30 - 49 ml/min) (see section 5.2).
Hepatic impairment
Xarelto is contraindicated in patients with hepatic disease associated with coagulopathy and clinically
relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see sections 4.3 and 5.2).
Elderly population
No dose adjustment (see sections 4.4 and 5.2).
Body weight
No dose adjustment (see sections 4.4 and 5.2).
Gender
No dose adjustment (see section 5.2).
Paediatric population
The safety and efficacy of Xarelto in children aged 0 to 18 years have not been established. No data
are available. Therefore, Xarelto is not recommended for use in children below 18 years of age.
Method of administration
For oral use.
Xarelto can be taken with or without food (see sections 4.5 and 5.2).
For patients who are unable to swallow whole tablets, Xarelto tablet may be crushed and mixed with
water or apple puree immediately prior to use and administered orally.
3
The crushed Xarelto tablet may also be given through gastric tubes after confirmation of the correct
gastric placement of the tube. The crushed tablet should be administered in a small amount of water
via a gastric tube after which it should be flushed with water (see section 5.2).
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Lesion or condition, if considered to be a significant risk for major bleeding. This may include current
or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent
brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage,
known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major
intraspinal or intracerebral vascular abnormalities.
Concomitant treatment with any other anticoagulants e.g. unfractionated heparin (UFH), low
molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral
anticoagulants (warfarin, dabigatran etexilate, apixaban, etc.) except under specific circumstances of
switching anticoagulant therapy (see section 4.2) or when UFH is given at doses necessary to maintain
an open central venous or arterial catheter (see section 4.5).
Concomitant treatment of ACS with antiplatelet therapy in patients with a prior stroke or a transient
ischaemic attack (TIA) (see section 4.4).
Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic
patients with Child Pugh B and C (see section 5.2).
Efficacy and safety of Xarelto has been investigated in combination with the antiplatelet agents aspirin
and clopidogrel/ticlopidine. Treatment in combination with other antiplatelet agents, e.g. prasugrel or
ticagrelor, has not been studied and is not recommended.
Clinical surveillance in line with anticoagulation practice is recommended throughout the treatment
period.
Haemorrhagic risk
As with other anticoagulants, patients taking Xarelto are to be carefully observed for signs of bleeding.
It is recommended to be used with caution in conditions with increased risk of haemorrhage. Xarelto
administration should be discontinued if severe haemorrhage occurs.
In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary) and
anaemia were seen more frequently during long term rivaroxaban treatment on top of single or dual
anti-platelet therapy. Thus, in addition to adequate clinical surveillance, laboratory testing of
haemoglobin/haematocrit could be of value to detect occult bleeding, as judged to be appropriate.
Several sub-groups of patients, as detailed below, are at increased risk of bleeding. Therefore, the use
of Xarelto in combination with dual antiplatelet therapy in patients at known increased risk for
bleeding should be balanced against the benefit in terms of prevention of atherothrombotic events. In
addition these patients are to be carefully monitored for signs and symptoms of bleeding complications
and anaemia after initiation of treatment (see section 4.8).
Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site.
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Although treatment with rivaroxaban does not require routine monitoring of exposure, rivaroxaban
levels measured with a calibrated quantitative anti-factor Xa assay may be useful in exceptional
situations where knowledge of rivaroxaban exposure may help to inform clinical decisions, e.g.,
overdose and emergency surgery (see sections 5.1 and 5.2).
Renal impairment
In patients with severe renal impairment (creatinine clearance < 30 ml/min) rivaroxaban plasma levels
may be significantly increased (1.6 fold on average) which may lead to an increased bleeding risk.
Xarelto is to be used with caution in patients with creatinine clearance 15 - 29 ml/min. Use is not
recommended in patients with creatinine clearance < 15 ml/min (see sections 4.2 and 5.2).
In patients with moderate renal impairment (creatinine clearance 30 - 49 ml/min) concomitantly
receiving other medicinal products which increase rivaroxaban plasma concentrations Xarelto is to be
used with caution (see section 4.5).
Care is to be taken if patients are treated concomitantly with medicinal products affecting haemostasis
such as non-steroidal anti-inflammatory medicinal products (NSAIDs), acetylsalicylic acid (ASA) and
platelet aggregation inhibitors. For patients at risk of ulcerative gastrointestinal disease an appropriate
prophylactic treatment may be considered (see section 4.5).
After an acute coronary syndrome patients on treatment with Xarelto and ASA or Xarelto and ASA
plus clopidogrel/ticlopidine should only receive concomitant treatment with NSAIDs if the benefit
outweighs the bleeding risk.
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symptoms of neurological impairment (e.g. numbness or weakness of the legs, bowel or bladder
dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior
to neuraxial intervention the physician should consider the potential benefit versus the risk in
anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. There is no clinical
experience with the use of 2.5 mg with ASA alone or with ASA plus clopidogrel or ticlopidine in
these situations.
To reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban and
neuraxial (epidural/spinal) anaesthesia or spinal puncture, consider the pharmacokinetic profile of
rivaroxaban. Placement or removal of an epidural catheter or lumbar puncture is best performed when
the anticoagulant effect of rivaroxaban is estimated to be low (see section 5.2). However, the exact
timing to reach a sufficiently low anticoagulant effect in each patient is not known.
Platelet aggregation inhibitors should be discontinued as suggested by the manufacturers prescribing
information.
Dosing recommendations before and after invasive procedures and surgical intervention
If an invasive procedure or surgical intervention is required, Xarelto 2.5 mg should be stopped at least
12 hours before the intervention, if possible and based on the clinical judgement of the physician. If a
patient is to undergo elective surgery and anti-platelet effect is not desired, platelet aggregation
inhibitors should be discontinued as directed by the manufacturers prescribing information.
If the procedure cannot be delayed the increased risk of bleeding should be assessed against the
urgency of the intervention.
Xarelto should be restarted as soon as possible after the invasive procedure or surgical intervention
provided the clinical situation allows and adequate haemostasis has been established as determined by
the treating physician (see section 5.2).
Elderly population
Increasing age may increase haemorrhagic risk (see section 5.2).
4.5 Interaction with other medicinal products and other forms of interaction
Active substances strongly inhibiting only one of the rivaroxaban elimination pathways, either
CYP3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent.
Clarithromycin (500 mg twice a day), for instance, considered as a strong CYP3A4 inhibitor and
moderate P-gp inhibitor, led to a 1.5 fold increase in mean rivaroxaban AUC and a 1.4 fold increase in
Cmax. This increase is not considered clinically relevant. (For patients with renal impairment: see
section 4.4).
Erythromycin (500 mg three times a day), which inhibits CYP3A4 and P-gp moderately, led to a
1.3 fold increase in mean rivaroxaban AUC and Cmax. This increase is not considered clinically
relevant.
In subjects with mild renal impairment erythromycin (500 mg three times a day) led to a 1.8 fold
increase in mean rivaroxaban AUC and 1.6 fold increase in C max when compared to subjects with
R
normal renal function. In subjects with moderate renal impairment, erythromycin led to a 2.0 fold
increase in mean rivaroxaban AUC and 1.6 fold increase in C max when compared to subjects with
R
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normal renal function. The effect of erythromycin is additive to that of renal impairment (see section
4.4).
Fluconazole (400 mg once daily), considered as a moderate CYP3A4 inhibitor, led to a 1.4 fold
increase in mean rivaroxaban AUC and a 1.3 fold increase in mean Cmax. This increase is not
considered clinically relevant. (For patients with renal impairment: see section 4.4).
Given the limited clinical data available with dronedarone, co-administration with rivaroxaban should
be avoided.
Anticoagulants
After combined administration of enoxaparin (40 mg single dose) with rivaroxaban (10 mg single
dose) an additive effect on anti-factor Xa activity was observed without any additional effects on
clotting tests (PT, aPTT). Enoxaparin did not affect the pharmacokinetics of rivaroxaban.
Due to the increased bleeding risk care is to be taken if patients are treated concomitantly with any
other anticoagulants (see sections 4.3 and 4.4).
Warfarin
Converting patients from the vitamin K antagonist warfarin (INR 2.0 to 3.0) to rivaroxaban (20 mg) or
from rivaroxaban (20 mg) to warfarin (INR 2.0 to 3.0) increased prothrombin time/INR (Neoplastin)
more than additively (individual INR values up to 12 may be observed), whereas effects on aPTT,
inhibition of factor Xa activity and endogenous thrombin potential were additive.
If it is desired to test the pharmacodynamic effects of rivaroxaban during the conversion period, anti-
factor Xa activity, PiCT, and Heptest can be used as these tests were not affected by warfarin. On the
fourth day after the last dose of warfarin, all tests (including PT, aPTT, inhibition of factor Xa activity
and ETP) reflected only the effect of rivaroxaban.
If it is desired to test the pharmacodynamic effects of warfarin during the conversion period, INR
measurement can be used at the Ctrough of rivaroxaban (24 hours after the previous intake of
rivaroxaban) as this test is minimally affected by rivaroxaban at this time point.
No pharmacokinetic interaction was observed between warfarin and rivaroxaban.
CYP3A4 inducers
Co-administration of rivaroxaban with the strong CYP3A4 inducer rifampicin led to an approximate
50 % decrease in mean rivaroxaban AUC, with parallel decreases in its pharmacodynamic effects. The
concomitant use of rivaroxaban with other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine,
phenobarbital or St. Johns Wort (Hypericum perforatum)) may also lead to reduced rivaroxaban
plasma concentrations. Therefore, concomitant administration of strong CYP3A4 inducers should be
avoided unless the patient is closely observed for signs and symptoms of thrombosis.
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atorvastatin (substrate of CYP3A4 and P-gp) or omeprazole (proton pump inhibitor). Rivaroxaban
neither inhibits nor induces any major CYP isoforms like CYP3A4.
No clinically relevant interaction with food was observed (see section 4.2).
Laboratory parameters
Clotting parameters (e.g. PT, aPTT, HepTest) are affected as expected by the mode of action of
rivaroxaban (see section 5.1).
Pregnancy
Safety and efficacy of Xarelto have not been established in pregnant women. Studies in animals have
shown reproductive toxicity (see section 5.3). Due to the potential reproductive toxicity, the intrinsic
risk of bleeding and the evidence that rivaroxaban passes the placenta, Xarelto is contraindicated
during pregnancy (see section 4.3).
Women of child-bearing potential should avoid becoming pregnant during treatment with rivaroxaban.
Breast feeding
Safety and efficacy of Xarelto have not been established in breast feeding women. Data from animals
indicate that rivaroxaban is secreted into milk. Therefore Xarelto is contraindicated during breast
feeding (see section 4.3). A decision must be made whether to discontinue breast feeding or to
discontinue/abstain from therapy.
Fertility
No specific studies with rivaroxaban in humans have been conducted to evaluate effects on fertility. In
a study on male and female fertility in rats no effects were seen (see section 5.3).
Xarelto has minor influence on the ability to drive and use machines. Adverse reactions like syncope
(frequency: uncommon) and dizziness (frequency: common) have been reported (see section 4.8).
Patients experiencing these adverse reactions should not drive or use machines.
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Table 1: Number of patients studied, maximum daily dose and treatment duration in phase III
studies
Indication Number Maximum daily Maximum
of dose treatment duration
patients*
Prevention of venous thromboembolism 6,097 10 mg 39 days
(VTE) in adult patients undergoing
elective hip or knee replacement surgery
Prevention of venous thromboembolism 3,997 10 mg 39 days
in medically ill patients
Treatment of DVT, PE and prevention 4,556 Day 1 - 21: 30 mg 21 months
of recurrence Day 22 and onwards:
20 mg
Prevention of stroke and systemic 7,750 20 mg 41 months
embolism in patients with non-valvular
atrial fibrillation
Prevention of atherothrombotic events in 10,225 5 mg or 10 mg 31 months
patients after an ACS respectively, co-
administered with
either ASA or ASA
plus clopidogrel or
ticlopidine
*Patients exposed to at least one dose of rivaroxaban
The most commonly reported adverse reactions in patients receiving rivaroxaban were bleedings (see
section 4.4. and Description of selected adverse reactions below). The most commonly reported
bleedings (4 %) were epistaxis (5.9 %) and gastrointestinal tract haemorrhage (4.2 %).
In total about 67 % of patients exposed to at least one dose of rivaroxaban were reported with
treatment emergent adverse events. About 22 % of the patients experienced adverse events considered
related to treatment as assessed by investigators. In patients treated with 10 mg Xarelto undergoing hip
or knee replacement surgery and in hospitalised medically ill patients, bleeding events occurred in
approximately 6.8 % and 12.6 % of patients, respectively, and anaemia occurred in approximately
5.9 % and 2.1 % of patients, respectively. In patients treated with either 15 mg twice daily Xarelto
followed by 20 mg once daily for treatment of DVT or PE, or with 20 mg once daily for prevention of
recurrent DVT and PE, bleeding events occurred in approximately 27.8 % of patients and anaemia
occurred in approximately 2.2 % of patients. In patients treated for prevention of stroke and systemic
embolism, bleeding of any type or severity was reported with an event rate of 28 per 100 patient years,
and anaemia with an event rate of 2.5 per 100 patient years. In patients treated for prevention of
atherothrombotic events after an acute coronary syndrome (ACS), bleeding of any type or severity was
reported with an event rate of 22 per 100 patient years. Anaemia was reported with an event rate of 1.4
per 100 patient years.
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Table 2: All treatment-emergent adverse reactions reported in patients in phase III studies
10
Common Uncommon Rare Not known
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dyspnoea and unexplained shock. In some cases as a consequence of anaemia, symptoms of cardiac
ischaemia like chest pain or angina pectoris have been observed.
Known complications secondary to severe bleeding such as compartment syndrome and renal failure
due to hypoperfusion have been reported for Xarelto. Therefore, the possibility of haemorrhage is to
be considered in evaluating the condition in any anticoagulated patient.
Post-marketing observations
The following adverse reactions have been reported post-marketing in temporal association with the
use of Xarelto. The frequency of these adverse reactions reported from post-marketing experience
cannot be estimated.
Immune system disorders: Angioedema and allergic oedema (In the pooled phase III trials, these
events were uncommon ( 1/1,000 to < 1/100)).
Hepatobiliary disorders: Cholestasis, Hepatitis (incl. hepatocellular injury) (In the pooled phase III
trials, these events were rare ( 1/10,000 to < 1/1,000)).
Blood and lymphatic system disorders: Thrombocytopenia (In the pooled phase III trials, these events
were uncommon ( 1/1,000 to < 1/100)).
4.9 Overdose
Rare cases of overdose up to 600 mg have been reported without bleeding complications or other
adverse reactions. Due to limited absorption a ceiling effect with no further increase in average plasma
exposure is expected at supratherapeutic doses of 50 mg rivaroxaban or above.
A specific antidote antagonising the pharmacodynamic effect of rivaroxaban is not available.
The use of activated charcoal to reduce absorption in case of rivaroxaban overdose may be considered.
Management of bleeding
Should a bleeding complication arise in a patient receiving rivaroxaban, the next rivaroxaban
administration should be delayed or treatment should be discontinued as appropriate. Rivaroxaban has
a half-life of approximately 5 to 13 hours (see section 5.2). Management should be individualised
according to the severity and location of the haemorrhage. Appropriate symptomatic treatment could
be used as needed, such as mechanical compression (e.g. for severe epistaxis), surgical haemostasis
with bleeding control procedures, fluid replacement and haemodynamic support, blood products
(packed red cells or fresh frozen plasma, depending on associated anaemia or coagulopathy) or
platelets.
If bleeding cannot be controlled by the above measures, administration of a specific procoagulant
reversal agent should be considered, such as prothrombin complex concentrate (PCC), activated
prothrombin complex concentrate (APCC) or recombinant factor VIIa (r-FVIIa). However, there is
currently very limited clinical experience with the use of these products in individuals receiving
rivaroxaban. The recommendation is also based on limited non-clinical data. Re-dosing of
recombinant factor VIIa shall be considered and titrated depending on improvement of bleeding.
Depending on local availability, a consultation with a coagulation expert should be considered in case
of major bleedings (see section 5.1).
Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban.
There is limited experience with tranexamic acid and no experience with aminocaproic acid and
aprotinin in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor
experience with the use of the systemic haemostatic desmopressin in individuals receiving
rivaroxaban. Due to the high plasma protein binding rivaroxaban is not expected to be dialysable.
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5. PHARMACOLOGICAL PROPERTIES
Mechanism of action
Rivaroxaban is a highly selective direct factor Xa inhibitor with oral bioavailability. Inhibition of
factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting
both thrombin formation and development of thrombi. Rivaroxaban does not inhibit thrombin
(activated factor II) and no effects on platelets have been demonstrated.
Pharmacodynamic effects
Dose-dependent inhibition of factor Xa activity was observed in humans. Prothrombin time (PT) is
influenced by rivaroxaban in a dose dependent way with a close correlation to plasma concentrations
(r value equals 0.98) if Neoplastin is used for the assay. Other reagents would provide different results.
The readout for PT is to be done in seconds, because the INR (International Normalised Ratio) is only
calibrated and validated for coumarins and cannot be used for any other anticoagulant.
In a clinical pharmacology study on the reversal of rivaroxaban pharmacodynamics in healthy adult
subjects (n=22), the effects of single doses (50 IU/kg) of two different types of PCCs, a 3-factor PCC
(Factors II, IX and X) and a 4-factor PCC (Factors II, VII, IX and X) were assessed. The 3-factor PCC
reduced mean Neoplastin PT values by approximately 1.0 second within 30 minutes, compared to
reductions of approximately 3.5 seconds observed with the 4-factor PCC. In contrast, the 3-factor PCC
had a greater and more rapid overall effect on reversing changes in endogenous thrombin generation
than the 4-factor PCC (see section 4.9).
The activated partial thomboplastin time (aPTT) and HepTest are also prolonged dose-dependently;
however, they are not recommended to assess the pharmacodynamic effect of rivaroxaban. There is no
need for monitoring of coagulation parameters during treatment with rivaroxaban in clinical routine.
However, if clinically indicated, rivaroxaban levels can be measured by calibrated quantitative anti-
factor-Xa tests (see section 5.2).
Both the 2.5 mg twice daily and the 5 mg twice daily regimens of rivaroxaban were effective in
further reducing the incidence of CV events on a background of standard antiplatelet care. The 2.5 mg
twice daily regimen reduced mortality, and there is evidence that the lower dose had lower bleeding
risks, therefore rivaroxaban 2.5 mg twice daily co-administered with acetylsalicylic acid (ASA) alone
or with ASA plus clopidogrel or ticlopidine is recommended for the prevention of atherothrombotic
events in adult patients after an ACS with elevated cardiac biomarkers.
Relative to placebo, Xarelto significantly reduced the primary composite endpoint of CV death, MI or
stroke. The benefit was driven by a reduction in CV death and MI and appeared early with a constant
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treatment effect over the entire treatment period (see Table 3 and Figure 1). Also the first secondary
endpoint (all cause death, MI or stroke) was reduced significantly. An additional retrospective
analysis showed a nominally significant reduction in the incidence rates of stent thrombosis compared
with placebo (see Table 3). The incidence rates for the principal safety outcome (non-CABG TIMI
major bleeding events) were higher in patients treated with Xarelto than in patients who received
placebo (see Table 5). However the incidence rates were balanced between Xarelto and placebo for
the components of fatal bleeding events, hypotension requiring treatment with intravenous inotropic
agents and surgical intervention for ongoing bleeding.
In Table 4 the efficacy results of patients undergoing percutaneous coronary intervention (PCI) are
presented. The safety results in this subgroup of patients undergoing PCI were comparable to the
overall safety results.
Patients with elevated biomarkers (troponin or CK-MB) and without a prior stroke/TIA constituted
80 % of the study population. The results of this patient population were also consistent with the
overall efficacy and safety results.
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Table 4: Efficacy results from phase III ATLAS ACS 2 TIMI 51 in patients undergoing PCI
Study Population Patients with recent acute coronary syndrome
undergoing PCI a)
15
a) safety population, on treatment b) vs. placebo; Log-Rank p-value
* statistically significant
Figure 1: Time to First Occurrence of Primary Efficacy Endpoint (CV death, MI or stroke)
15
XARELTO 2.5 mg twice daily
14 Placebo
13
12
11
Cumulative Event Rate (%)
10
Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with
Xarelto in one or more subsets of the paediatric population in the treatment of thromboembolic events.
The European Medicines Agency has waived the obligation to submit the results of studies with
Xarelto in all subsets of the paediatric population in the prevention of thromboembolic events (see
section 4.2 for information on paediatric use).
Absorption
Rivaroxaban is rapidly absorbed with maximum concentrations (Cmax) appearing 2 - 4 hours after
tablet intake.
Oral absorption of rivaroxaban is almost complete and oral bioavailability is high (80 - 100 %) for the
2.5 mg and 10 mg tablet dose, irrespective of fasting/fed conditions. Intake with food does not affect
rivaroxaban AUC or Cmax at the 2.5 mg and 10 mg dose. Rivaroxaban 2.5 mg and 10 mg tablets can be
taken with or without food.
Rivaroxaban pharmacokinetics are approximately linear up to about 15 mg once daily. At higher doses
rivaroxaban displays dissolution limited absorption with decreased bioavailability and decreased
absorption rate with increased dose. This is more marked in fasting state than in fed state. Variability
in rivaroxaban pharmacokinetics is moderate with inter-individual variability (CV %) ranging from
30 % to 40 %.
Absorption of rivaroxaban is dependent on the site of its release in the gastrointestinal tract. A 29%
and 56% decrease in AUC and Cmax compared to tablet was reported when rivaroxaban granulate is
released in the proximal small intestine. Exposure is further reduced when rivaroxaban is released in
the distal small intestine, or ascending colon. Therefore, administration of rivaroxaban distal to the
stomach should be avoided since this can result in reduced absorption and related rivaroxaban
exposure.
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Bioavailability (AUC and Cmax) was comparable for 20 mg rivaroxaban administered orally as a
crushed tablet mixed in apple puree, or suspended in water and administered via a gastric tube
followed by a liquid meal, compared to a whole tablet. Given the predictable, dose-proportional
pharmacokinetic profile of rivaroxaban, the bioavailability results from this study are likely applicable
to lower rivaroxaban doses.
Distribution
Plasma protein binding in humans is high at approximately 92 % to 95 %, with serum albumin being
the main binding component. The volume of distribution is moderate with Vss being approximately
50 litres.
Special populations
Gender
There were no clinically relevant differences in pharmacokinetics and pharmacodynamics between
male and female patients.
Elderly population
Elderly patients exhibited higher plasma concentrations than younger patients, with mean AUC values
being approximately 1.5 fold higher, mainly due to reduced (apparent) total and renal clearance. No
dose adjustment is necessary.
Inter-ethnic differences
No clinically relevant inter-ethnic differences among Caucasian, African-American, Hispanic,
Japanese or Chinese patients were observed regarding rivaroxaban pharmacokinetics and
pharmacodynamics.
Hepatic impairment
Cirrhotic patients with mild hepatic impairment (classified as Child Pugh A) exhibited only minor
changes in rivaroxaban pharmacokinetics (1.2 fold increase in rivaroxaban AUC on average), nearly
comparable to their matched healthy control group. In cirrhotic patients with moderate hepatic
impairment (classified as Child Pugh B), rivaroxaban mean AUC was significantly increased by
2.3 fold compared to healthy volunteers. Unbound AUC was increased 2.6 fold. These patients also
had reduced renal elimination of rivaroxaban, similar to patients with moderate renal impairment.
There are no data in patients with severe hepatic impairment.
The inhibition of factor Xa activity was increased by a factor of 2.6 in patients with moderate hepatic
impairment as compared to healthy volunteers; prolongation of PT was similarly increased by a factor
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of 2.1. Patients with moderate hepatic impairment were more sensitive to rivaroxaban resulting in a
steeper PK/PD relationship between concentration and PT.
Xarelto is contraindicated in patients with hepatic disease associated with coagulopathy and clinically
relevant bleeding risk, including cirrhotic patients with Child Pugh B and C (see section 4.3).
Renal impairment
There was an increase in rivaroxaban exposure correlated to decrease in renal function, as assessed via
creatinine clearance measurements. In individuals with mild (creatinine clearance 50 - 80 ml/min),
moderate (creatinine clearance 30 - 49 ml/min) and severe (creatinine clearance 15 - 29 ml/min) renal
impairment, rivaroxaban plasma concentrations (AUC) were increased 1.4, 1.5 and 1.6 fold
respectively. Corresponding increases in pharmacodynamic effects were more pronounced. In
individuals with mild, moderate and severe renal impairment the overall inhibition of factor Xa
activity was increased by a factor of 1.5, 1.9 and 2.0 respectively as compared to healthy volunteers;
prolongation of PT was similarly increased by a factor of 1.3, 2.2 and 2.4 respectively. There are no
data in patients with creatinine clearance < 15 ml/min.
Due to the high plasma protein binding rivaroxaban is not expected to be dialysable.
Use is not recommended in patients with creatinine clearance < 15 ml/min. Xarelto is to be used with
caution in patients with creatinine clearance 15 - 29 ml/min (see section 4.4).
Pharmacokinetic/pharmacodynamic relationship
The pharmacokinetic/pharmacodynamic (PK/PD) relationship between rivaroxaban plasma
concentration and several PD endpoints (factor-Xa inhibition, PT, aPTT, Heptest) has been evaluated
after administration of a wide range of doses (5 - 30 mg twice a day). The relationship between
rivaroxaban concentration and factor-Xa activity was best described by an Emax model. For PT, the
linear intercept model generally described the data better. Depending on the different PT reagents
used, the slope differed considerably. When Neoplastin PT was used, baseline PT was about 13 s and
the slope was around 3 to 4 s/(100 g/l). The results of the PK/PD analyses in Phase II and III were
consistent with the data established in healthy subjects.
Paediatric population
Safety and efficacy have not been established for children and adolescents up to 18 years.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, single dose toxicity, phototoxicity, genotoxicity, carcinogenic potential and juvenile
toxicity.
Effects observed in repeat-dose toxicity studies were mainly due to the exaggerated pharmacodynamic
activity of rivaroxaban. In rats, increased IgG and IgA plasma levels were seen at clinically relevant
exposure levels.
In rats, no effects on male or female fertility were seen. Animal studies have shown reproductive
toxicity related to the pharmacological mode of action of rivaroxaban (e.g. haemorrhagic
complications). Embryo-foetal toxicity (post-implantation loss, retarded/progressed ossification,
hepatic multiple light coloured spots) and an increased incidence of common malformations as well as
placental changes were observed at clinically relevant plasma concentrations. In the pre- and post-
natal study in rats, reduced viability of the offspring was observed at doses that were toxic to the dams.
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6. PHARMACEUTICAL PARTICULARS
Tablet core:
Microcrystalline cellulose
Croscarmellose sodium
Lactose monohydrate
Hypromellose
Sodium laurilsulfate
Magnesium stearate
Film-coat:
Macrogol 3350
Hypromellose
Titanium dioxide (E 171)
Iron oxide yellow (E 172)
6.2 Incompatibilities
Not applicable.
3 years
This medicinal product does not require any special storage conditions.
PP/Aluminium foil blisters in cartons of 14, 28, 30, 56, 60, 98, 168 or 196 film-coated tablets or
perforated unit dose blisters in cartons of 10 x 1 or 100 x 1 or in multipacks containing 100 (10 packs
of 10 x 1) film-coated tablets.
Bayer Pharma AG
13342 Berlin
Germany
EU/1/08/472/025-035
19
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
{MM/YYYY}
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu.
20
This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
See section 4.8 for how to report adverse reactions.
3. PHARMACEUTICAL FORM
4. CLINICAL PARTICULARS
Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee
replacement surgery.
Posology
The recommended dose is 10 mg rivaroxaban taken orally once daily. The initial dose should be taken
6 to 10 hours after surgery, provided that haemostasis has been established.
The duration of treatment depends on the individual risk of the patient for venous thromboembolism
which is determined by the type of orthopaedic surgery.
For patients undergoing major hip surgery, a treatment duration of 5 weeks is recommended.
For patients undergoing major knee surgery, a treatment duration of 2 weeks is recommended.
If a dose is missed the patient should take Xarelto immediately and then continue the following day
with once daily intake as before.
21
In patients converting from Xarelto to VKA, VKA should be given concurrently until the INR is 2.0.
For the first two days of the conversion period, standard initial dosing of VKA should be used
followed by VKA dosing, as guided by INR testing. While patients are on both Xarelto and VKA the
INR should not be tested earlier than 24 hours after the previous dose but prior to the next dose of
Xarelto. Once Xarelto is discontinued INR testing may be done reliably at least 24 hours after the last
dose (see sections 4.5 and 5.2).
Special populations
Renal impairment
Limited clinical data for patients with severe renal impairment (creatinine clearance 15 - 29 ml/min)
indicate that rivaroxaban plasma concentrations are significantly increased. Therefore, Xarelto is to be
used with caution in these patients. Use is not recommended in patients with creatinine clearance
< 15 ml/min (see sections 4.4 and 5.2).
No dose adjustment is necessary in patients with mild renal impairment (creatinine clearance 50 -
80 ml/min) or moderate renal impairment (creatinine clearance 30 - 49 ml/min) (see section 5.2).
Hepatic impairment
Xarelto is contraindicated in patients with hepatic disease associated with coagulopathy and clinically
relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see sections 4.3 and 5.2).
Elderly population
No dose adjustment (see section 5.2).
Body weight
No dose adjustment (see section 5.2).
Gender
No dose adjustment (see section 5.2).
Paediatric population
The safety and efficacy of Xarelto in children aged 0 to 18 years have not been established. No data
are available. Therefore, Xarelto is not recommended for use in children below 18 years of age.
Method of administration
For oral use.
Xarelto can be taken with or without food (see sections 4.5 and 5.2).
For patients who are unable to swallow whole tablets, Xarelto tablet may be crushed and mixed with
water or apple puree immediately prior to use and administered orally.
The crushed Xarelto tablet may also be given through gastric tubes after confirmation of the correct
gastric placement of the tube. The crushed tablet should be administered in a small amount of water
via a gastric tube after which it should be flushed with water (see section 5.2).
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
22
Lesion or condition, if considered to be a significant risk for major bleeding. This may include current
or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent
brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage,
known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major
intraspinal or intracerebral vascular abnormalities.
Concomitant treatment with any other anticoagulants e.g. unfractionated heparin (UFH), low
molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral
anticoagulants (warfarin, dabigatran etexilate, apixaban, etc.) except under specific circumstances of
switching anticoagulant therapy (see section 4.2) or when UFH is given at doses necessary to maintain
an open central venous or arterial catheter (see section 4.5).
Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic
patients with Child Pugh B and C (see section 5.2).
Haemorrhagic risk
Several sub-groups of patients, as detailed below, are at increased risk of bleeding. These patients are
to be carefully monitored for signs and symptoms of bleeding complications and anaemia after
initiation of treatment (see section 4.8). This may be done by regular physical examination of the
patients, close observation of the surgical wound drainage and periodic measurements of haemoglobin.
Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site.
Although treatment with rivaroxaban does not require routine monitoring of exposure, rivaroxaban
levels measured with a calibrated quantitative anti-factor Xa assay may be useful in exceptional
situations where knowledge of rivaroxaban exposure may help to inform clinical decisions, e.g.,
overdose and emergency surgery (see sections 5.1 and 5.2).
Renal impairment
In patients with severe renal impairment (creatinine clearance < 30 ml/min) rivaroxaban plasma levels
may be significantly increased (1.6-fold on average) which may lead to an increased bleeding risk.
Xarelto is to be used with caution in patients with creatinine clearance 15 - 29 ml/min. Use is not
recommended in patients with creatinine clearance < 15 ml/min (see sections 4.2 and 5.2).
In patients with moderate renal impairment (creatinine clearance 30 - 49 ml/min) concomitantly
receiving other medicinal products which increase rivaroxaban plasma concentrations Xarelto is to be
used with caution (see section 4.5).
Care is to be taken if patients are treated concomitantly with medicinal products affecting haemostasis
such as non-steroidal anti-inflammatory medicinal products (NSAIDs), acetylsalicylic acid (ASA) and
platelet aggregation inhibitors. For patients at risk of ulcerative gastrointestinal disease an appropriate
prophylactic treatment may be considered (see section 4.5).
23
Other haemorrhagic risk factors
As with other antithrombotics, rivaroxaban is to be used with caution in patients with an increased
bleeding risk such as:
congenital or acquired bleeding disorders
uncontrolled severe arterial hypertension
other gastrointestinal disease without active ulceration that can potentially lead to bleeding
complications (e.g. inflammatory bowel disease, oesophagitis, gastritis and gastroesophageal
reflux disease)
vascular retinopathy
bronchiectasis or history of pulmonary bleeding
Dosing recommendations before and after invasive procedures and surgical intervention other than
elective hip or knee replacement surgery
If an invasive procedure or surgical intervention is required, Xarelto 10 mg should be stopped at least
24 hours before the intervention, if possible and based on the clinical judgement of the physician.
If the procedure cannot be delayed the increased risk of bleeding should be assessed against the
urgency of the intervention.
Xarelto should be restarted as soon as possible after the invasive procedure or surgical intervention
provided the clinical situation allows and adequate haemostasis has been established as determined by
the treating physician (see section 5.2).
Elderly population
Increasing age may increase haemorrhagic risk (see section 5.2).
24
4.5 Interaction with other medicinal products and other forms of interaction
Active substances strongly inhibiting only one of the rivaroxaban elimination pathways, either
CYP3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent.
Clarithromycin (500 mg twice a day), for instance, considered as a strong CYP3A4 inhibitor and
moderate P-gp inhibitor, led to a 1.5 fold increase in mean rivaroxaban AUC and a 1.4 fold increase in
Cmax. This increase is not considered clinically relevant. (For patients with renal impairment: see
section 4.4).
Erythromycin (500 mg three times a day), which inhibits CYP3A4 and P-gp moderately, led to a
1.3 fold increase in mean rivaroxaban AUC and Cmax. This increase is not considered clinically
relevant.
In subjects with mild renal impairment erythromycin (500 mg three times a day) led to a 1.8 fold
increase in mean rivaroxaban AUC and 1.6 fold increase in C max when compared to subjects with
R
normal renal function. In subjects with moderate renal impairment, erythromycin led to a 2.0 fold
increase in mean rivaroxaban AUC and 1.6 fold increase in C max when compared to subjects with
R
normal renal function. The effect of erythromycin is additive to that of renal impairment (see section
4.4).
Fluconazole (400 mg once daily), considered as a moderate CYP3A4 inhibitor, led to a 1.4 fold
increase in mean rivaroxaban AUC and a 1.3 fold increase in mean Cmax. This increase is not
considered clinically relevant. (For patients with renal impairment: see section 4.4).
Given the limited clinical data available with dronedarone, co-administration with rivaroxaban should
be avoided.
Anticoagulants
After combined administration of enoxaparin (40 mg single dose) with rivaroxaban (10 mg single
dose) an additive effect on anti-factor Xa activity was observed without any additional effects on
clotting tests (PT, aPTT). Enoxaparin did not affect the pharmacokinetics of rivaroxaban.
Due to the increased bleeding risk care is to be taken if patients are treated concomitantly with any
other anticoagulants (see sections 4.3 and 4.4).
25
Warfarin
Converting patients from the vitamin K antagonist warfarin (INR 2.0 to 3.0) to rivaroxaban (20 mg) or
from rivaroxaban (20 mg) to warfarin (INR 2.0 to 3.0) increased prothrombin time/INR (Neoplastin)
more than additively (individual INR values up to 12 may be observed), whereas effects on aPTT,
inhibition of factor Xa activity and endogenous thrombin potential were additive.
If it is desired to test the pharmacodynamic effects of rivaroxaban during the conversion period, anti-
factor Xa activity, PiCT, and Heptest can be used as these tests were not affected by warfarin. On the
fourth day after the last dose of warfarin, all tests (including PT, aPTT, inhibition of factor Xa activity
and ETP) reflected only the effect of rivaroxaban.
If it is desired to test the pharmacodynamic effects of warfarin during the conversion period, INR
measurement can be used at the Ctrough of rivaroxaban (24 hours after the previous intake of
rivaroxaban) as this test is minimally affected by rivaroxaban at this time point.
No pharmacokinetic interaction was observed between warfarin and rivaroxaban.
CYP3A4 inducers
Co-administration of rivaroxaban with the strong CYP3A4 inducer rifampicin led to an approximate
50 % decrease in mean rivaroxaban AUC, with parallel decreases in its pharmacodynamic effects. The
concomitant use of rivaroxaban with other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine,
phenobarbital or St. Johns Wort (Hypericum perforatum)) may also lead to reduced rivaroxaban
plasma concentrations. Therefore, concomitant administration of strong CYP3A4 inducers should be
avoided unless the patient is closely observed for signs and symptoms of thrombosis.
Laboratory parameters
Clotting parameters (e.g. PT, aPTT, HepTest) are affected as expected by the mode of action of
rivaroxaban (see section 5.1).
Pregnancy
Safety and efficacy of Xarelto have not been established in pregnant women. Studies in animals have
shown reproductive toxicity (see section 5.3). Due to the potential reproductive toxicity, the intrinsic
risk of bleeding and the evidence that rivaroxaban passes the placenta, Xarelto is contraindicated
during pregnancy (see section 4.3).
Women of child bearing potential should avoid becoming pregnant during treatment with rivaroxaban.
Breast feeding
Safety and efficacy of Xarelto have not been established in breast feeding women. Data from animals
indicate that rivaroxaban is secreted into milk. Therefore Xarelto is contraindicated during breast
feeding (see section 4.3). A decision must be made whether to discontinue breast feeding or to
discontinue/abstain from therapy.
Fertility
No specific studies with rivaroxaban in humans have been conducted to evaluate effects on fertility. In
a study on male and female fertility in rats no effects were seen (see section 5.3).
Xarelto has minor influence on the ability to drive and use machines. Adverse reactions like syncope
(frequency: uncommon) and dizziness (frequency: common) have been reported (see section 4.8).
Patients experiencing these adverse reactions should not drive or use machines.
26
4.8 Undesirable effects
Table 1: Number of patients studied, maximum daily dose and treatment duration in phase III
studies
Indication Number Maximum daily Maximum
of dose treatment duration
patients*
Prevention of venous thromboembolism 6,097 10 mg 39 days
(VTE) in adult patients undergoing
elective hip or knee replacement surgery
Prevention of venous thromboembolism 3,997 10 mg 39 days
in medically ill patients
Treatment of DVT, PE and prevention 4,556 Day 1 - 21: 30 mg 21 months
of recurrence Day 22 and onwards:
20 mg
Prevention of stroke and systemic 7,750 20 mg 41 months
embolism in patients with non-valvular
atrial fibrillation
Prevention of atherothrombotic events in 10,225 5 mg or 10 mg 31 months
patients after an ACS respectively, co-
administered with
either ASA or ASA
plus clopidogrel or
ticlopidine
*Patients exposed to at least one dose of rivaroxaban
The most commonly reported adverse reactions in patients receiving rivaroxaban were bleedings (see
section 4.4. and Description of selected adverse reactions below). The most commonly reported
bleedings (4 %) were epistaxis (5.9 %) and gastrointestinal tract haemorrhage (4.2 %).
In total about 67% of patients exposed to at least one dose of rivaroxaban were reported with treatment
emergent adverse events. About 22 % of the patients experienced adverse events considered related to
treatment as assessed by investigators. In patients treated with 10 mg Xarelto undergoing hip or knee
replacement surgery and in hospitalised medically ill patients, bleeding events occurred in
approximately 6.8 % and 12.6 % of patients, respectively, and anaemia occurred in approximately
5.9 % and 2.1 % of patients, respectively. In patients treated with either 15 mg twice daily Xarelto
followed by 20 mg once daily for treatment of DVT or PE, or with 20 mg once daily for prevention of
recurrent DVT and PE, bleeding events occurred in approximately 27.8 % of patients and anaemia
occurred in approximately 2.2 % of patients. In patients treated for prevention of stroke and systemic
embolism, bleeding of any type or severity was reported with an event rate of 28 per 100 patient years,
and anaemia with an event rate of 2.5 per 100 patient years. In patients treated for prevention of
atherothrombotic events after an acute coronary syndrome (ACS), bleeding of any type or severity was
reported with an event rate of 22 per 100 patient years. Anaemia was reported with an event rate of 1.4
per 100 patient years.
27
Frequencies are defined as:
very common ( 1/10)
common ( 1/100 to < 1/10)
uncommon ( 1/1,000 to < 1/100)
rare ( 1/10,000 to < 1/1,000)
very rare ( < 1/10,000)
not known (cannot be estimated from the available data)
Table 2: All treatment-emergent adverse reactions reported in patients in phase III studies
28
Common Uncommon Rare Not known
29
Description of selected adverse reactions
Due to the pharmacological mode of action, the use of Xarelto may be associated with an increased
risk of occult or overt bleeding from any tissue or organ which may result in post haemorrhagic
anaemia. The signs, symptoms, and severity (including fatal outcome) will vary according to the
location and degree or extent of the bleeding and/or anaemia (see section 4.9 Management of
bleeding). In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito
urinary) and anaemia were seen more frequently during long term rivaroxaban treatment compared
with VKA treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of
haemoglobin/haematocrit could be of value to detect occult bleeding, as judged to be appropriate. The
risk of bleedings may be increased in certain patient groups e.g. those patients with uncontrolled
severe arterial hypertension and/or on concomitant treatment affecting haemostasis (see Haemorrhagic
risk in section 4.4). Menstrual bleeding may be intensified and/or prolonged. Haemorrhagic
complications may present as weakness, paleness, dizziness, headache or unexplained swelling,
dyspnoea and unexplained shock. In some cases as a consequence of anaemia, symptoms of cardiac
ischaemia like chest pain or angina pectoris have been observed.
Known complications secondary to severe bleeding such as compartment syndrome and renal failure
due to hypoperfusion have been reported for Xarelto. Therefore, the possibility of haemorrhage is to
be considered in evaluating the condition in any anticoagulated patient.
Post-marketing observations
The following adverse reactions have been reported post-marketing in temporal association with the
use of Xarelto. The frequency of these adverse reactions reported from post-marketing experience
cannot be estimated.
Immune system disorders: Angioedema and allergic oedema (In the pooled phase III trials, these
events were uncommon ( 1/1,000 to < 1/100)).
Hepatobiliary disorders: Cholestasis, Hepatitis (incl. hepatocellular injury) (In the pooled phase III
trials, these events were rare ( 1/10,000 to < 1/1,000)).
Blood and lymphatic system disorders: Thrombocytopenia (In the pooled phase III trials, these events
were uncommon ( 1/1,000 to < 1/100)).
4.9 Overdose
Rare cases of overdose up to 600 mg have been reported without bleeding complications or other
adverse reactions. Due to limited absorption a ceiling effect with no further increase in average plasma
exposure is expected at supratherapeutic doses of 50 mg rivaroxaban or above.
A specific antidote antagonising the pharmacodynamic effect of rivaroxaban is not available.
The use of activated charcoal to reduce absorption in case of rivaroxaban overdose may be considered.
Management of bleeding
Should a bleeding complication arise in a patient receiving rivaroxaban, the next rivaroxaban
administration should be delayed or treatment should be discontinued as appropriate. Rivaroxaban has
a half-life of approximately 5 to 13 hours (see section 5.2). Management should be individualised
according to the severity and location of the haemorrhage. Appropriate symptomatic treatment could
be used as needed, such as mechanical compression (e.g. for severe epistaxis), surgical haemostasis
with bleeding control procedures, fluid replacement and haemodynamic support, blood products
(packed red cells or fresh frozen plasma, depending on associated anaemia or coagulopathy) or
platelets.
If bleeding cannot be controlled by the above measures, administration of a specific procoagulant
reversal agent should be considered, such as prothrombin complex concentrate (PCC), activated
prothrombin complex concentrate (APCC) or recombinant factor VIIa (r-FVIIa). However, there is
currently very limited clinical experience with the use of these products in individuals receiving
30
rivaroxaban. The recommendation is also based on limited non-clinical data. Re-dosing of
recombinant factor VIIa shall be considered and titrated depending on improvement of bleeding.
Depending on local availability, a consultation with a coagulation expert should be considered in case
of major bleedings (see section 5.1).
Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban.
There is limited experience with tranexamic acid and no experience with aminocaproic acid and
aprotinin in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor
experience with the use of the systemic haemostatic desmopressin in individuals receiving
rivaroxaban. Due to the high plasma protein binding rivaroxaban is not expected to be dialysable.
5. PHARMACOLOGICAL PROPERTIES
Mechanism of action
Rivaroxaban is a highly selective direct factor Xa inhibitor with oral bioavailability. Inhibition of
factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting
both thrombin formation and development of thrombi. Rivaroxaban does not inhibit thrombin
(activated factor II) and no effects on platelets have been demonstrated.
Pharmacodynamic effects
Dose-dependent inhibition of factor Xa activity was observed in humans. Prothrombin time (PT) is
influenced by rivaroxaban in a dose dependent way with a close correlation to plasma concentrations
(r value equals 0.98) if Neoplastin is used for the assay. Other reagents would provide different results.
The readout for PT is to be done in seconds, because the INR (International Normalised Ratio) is only
calibrated and validated for coumarins and cannot be used for any other anticoagulant. In patients
undergoing major orthopaedic surgery, the 5/95 percentiles for PT (Neoplastin) 2 - 4 hours after tablet
intake (i.e. at the time of maximum effect) ranged from 13 to 25 s (baseline values before surgery
12 to 15s).
In a clinical pharmacology study on the reversal of rivaroxaban pharmacodynamics in healthy adult
subjects (n=22), the effects of single doses (50 IU/kg) of two different types of PCCs, a 3-factor PCC
(Factors II, IX and X) and a 4-factor PCC (Factors II, VII, IX and X) were assessed. The 3-factor PCC
reduced mean Neoplastin PT values by approximately 1.0 second within 30 minutes, compared to
reductions of approximately 3.5 seconds observed with the 4-factor PCC. In contrast, the 3-factor PCC
had a greater and more rapid overall effect on reversing changes in endogenous thrombin generation
than the 4-factor PCC (see section 4.9).
The activated partial thomboplastin time (aPTT) and HepTest are also prolonged dose-dependently;
however, they are not recommended to assess the pharmacodynamic effect of rivaroxaban. There is no
need for monitoring of coagulation parameters during treatment with rivaroxaban in clinical routine.
However, if clinically indicated rivaroxaban levels can be measured by calibrated quantitative anti-
factor Xa tests (see section 5.2).
31
endpoints. Furthermore, in all three studies the rate of symptomatic VTE (symptomatic DVT, non-
fatal PE, VTE-related death) was lower in rivaroxaban treated patients compared to patients treated
with enoxaparin.
The main safety endpoint, major bleeding, showed comparable rates for patients treated with
rivaroxaban 10 mg compared to enoxaparin 40 mg.
Table 3: Efficacy and safety results from phase III clinical studies
RECORD 1 RECORD 2 RECORD 3
Study 4,541 patients undergoing total hip 2,509 patients undergoing total hip 2,531 patients undergoing total knee
Population replacement surgery replacement surgery replacement surgery
Treatment Rivaroxaban Enoxaparin p Rivaroxaban Enoxaparin p Rivaroxaban Enoxaparin p
dose and 10 mg od 40 mg od 10 mg od 40 mg od 10 mg od 40 mg od
duration 35 4 days 35 4 days 35 4 days 12 2 days 12 2 days 12 2 days
after
surgery
Total VTE 18 (1.1 %) 58 (3.7 %) < 0.001 17 (2.0 %) 81 (9.3 %) < 0.001 79 (9.6 %) 166 (18.9 %) < 0.001
Major 4 (0.2 %) 33 (2.0 %) < 0.001 6 (0.6 %) 49 (5.1 %) < 0.001 9 (1.0 %) 24 (2.6 %) 0.01
VTE
Sympto- 6 (0.4 %) 11 (0.7 %) 3 (0.4 %) 15 (1.7 %) 8 (1.0 %) 24 (2.7 %)
matic VTE
Major 6 (0.3 %) 2 (0.1 %) 1 (0.1 %) 1 (0.1 %) 7 (0.6 %) 6 (0.5 %)
bleedings
The analysis of the pooled results of the phase III trials corroborated the data obtained in the
individual studies regarding reduction of total VTE, major VTE and symptomatic VTE with
rivaroxaban 10 mg once daily compared to enoxaparin 40 mg once daily.
Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with
Xarelto in one or more subsets of the paediatric population in the treatment of thromboembolic events.
The European Medicines Agency has waived the obligation to submit the results of studies with
Xarelto in all subsets of the paediatric population in the prevention of thromboembolic events (see
section 4.2 for information on paediatric use).
Absorption
Rivaroxaban is rapidly absorbed with maximum concentrations (Cmax) appearing 2 - 4 hours after
tablet intake.
Oral absorption of rivaroxaban is almost complete and oral bioavailability is high (80 - 100%) for the
2.5 mg and 10 mg tablet dose, irrespective of fasting/fed conditions. Intake with food does not affect
rivaroxaban AUC or Cmax at the 2.5 mg and 10 mg dose. Rivaroxaban 2.5 mg and 10 mg tablets can be
taken with or without food. Rivaroxaban pharmacokinetics are approximately linear up to about 15 mg
once daily. At higher doses rivaroxaban displays dissolution limited absorption with decreased
bioavailability and decreased absorption rate with increased dose. This is more marked in fasting state
than in fed state. Variability in rivaroxaban pharmacokinetics is moderate with inter-individual
32
variability (CV %) ranging from 30 % to 40 %, apart from on the day of surgery and the following day
when variability in exposure is high (70 %).
Absorption of rivaroxaban is dependent on the site of its release in the gastrointestinal tract. A 29%
and 56% decrease in AUC and Cmax compared to tablet was reported when rivaroxaban granulate is
released in the proximal small intestine. Exposure is further reduced when rivaroxaban is released in
the distal small intestine, or ascending colon. Therefore, administration of rivaroxaban distal to the
stomach should be avoided since this can result in reduced absorption and related rivaroxaban
exposure.
Bioavailability (AUC and Cmax) was comparable for 20 mg rivaroxaban administered orally as a
crushed tablet mixed in apple puree, or suspended in water and administered via a gastric tube
followed by a liquid meal, compared to a whole tablet. Given the predictable, dose-proportional
pharmacokinetic profile of rivaroxaban, the bioavailability results from this study are likely applicable
to lower rivaroxaban doses.
Distribution
Plasma protein binding in humans is high at approximately 92 % to 95 %, with serum albumin being
the main binding component. The volume of distribution is moderate with Vss being approximately
50 litres.
Special populations
Gender
There were no clinically relevant differences in pharmacokinetics and pharmacodynamics between
male and female patients.
Elderly population
Elderly patients exhibited higher plasma concentrations than younger patients, with mean AUC values
being approximately 1.5 fold higher, mainly due to reduced (apparent) total and renal clearance. No
dose adjustment is necessary.
Inter-ethnic differences
No clinically relevant inter-ethnic differences among Caucasian, African-American, Hispanic,
Japanese or Chinese patients were observed regarding rivaroxaban pharmacokinetics and
pharmacodynamics.
Hepatic impairment
Cirrhotic patients with mild hepatic impairment (classified as Child Pugh A) exhibited only minor
changes in rivaroxaban pharmacokinetics (1.2 fold increase in rivaroxaban AUC on average), nearly
33
comparable to their matched healthy control group. In cirrhotic patients with moderate hepatic
impairment (classified as Child Pugh B), rivaroxaban mean AUC was significantly increased by
2.3 fold compared to healthy volunteers. Unbound AUC was increased 2.6 fold. These patients also
had reduced renal elimination of rivaroxaban, similar to patients with moderate renal impairment.
There are no data in patients with severe hepatic impairment.
The inhibition of factor Xa activity was increased by a factor of 2.6 in patients with moderate hepatic
impairment as compared to healthy volunteers; prolongation of PT was similarly increased by a factor
of 2.1. Patients with moderate hepatic impairment were more sensitive to rivaroxaban resulting in a
steeper PK/PD relationship between concentration and PT.
Xarelto is contraindicated in patients with hepatic disease associated with coagulopathy and clinically
relevant bleeding risk, including cirrhotic patients with Child Pugh B and C (see section 4.3).
Renal impairment
There was an increase in rivaroxaban exposure correlated to decrease in renal function, as assessed via
creatinine clearance measurements. In individuals with mild (creatinine clearance 50 - 80 ml/min),
moderate (creatinine clearance 30 - 49 ml/min) and severe (creatinine clearance 15 - 29 ml/min) renal
impairment, rivaroxaban plasma concentrations (AUC) were increased 1.4, 1.5 and 1.6 fold
respectively. Corresponding increases in pharmacodynamic effects were more pronounced. In
individuals with mild, moderate and severe renal impairment the overall inhibition of factor Xa
activity was increased by a factor of 1.5, 1.9 and 2.0 respectively as compared to healthy volunteers;
prolongation of PT was similarly increased by a factor of 1.3, 2.2 and 2.4 respectively. There are no
data in patients with creatinine clearance < 15 ml/min.
Due to the high plasma protein binding rivaroxaban is not expected to be dialysable.
Use is not recommended in patients with creatinine clearance < 15 ml/min. Xarelto is to be used with
caution in patients with creatinine clearance 15 - 29 ml/min (see section 4.4).
Pharmacokinetic/pharmacodynamic relationship
The pharmacokinetic/pharmacodynamic (PK/PD) relationship between rivaroxaban plasma
concentration and several PD endpoints (factor Xa inhibition, PT, aPTT, Heptest) has been evaluated
after administration of a wide range of doses (5 - 30 mg twice a day). The relationship between
rivaroxaban concentration and factor Xa activity was best described by an Emax model. For PT, the
linear intercept model generally described the data better. Depending on the different PT reagents
used, the slope differed considerably. When Neoplastin PT was used, baseline PT was about 13 s and
the slope was around 3 to 4 s/(100 g/l). The results of the PK/PD analyses in Phase II and III were
consistent with the data established in healthy subjects. In patients, baseline factor Xa and PT were
influenced by the surgery resulting in a difference in the concentration-PT slope between the day post-
surgery and steady state.
Paediatric population
Safety and efficacy have not been established for children and adolescents up to 18 years.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, single dose toxicity, phototoxicity, genotoxicity, carcinogenic potential and juvenile
toxicity.
Effects observed in repeat-dose toxicity studies were mainly due to the exaggerated pharmacodynamic
activity of rivaroxaban. In rats, increased IgG and IgA plasma levels were seen at clinically relevant
exposure levels.
In rats, no effects on male or female fertility were seen. Animal studies have shown reproductive
toxicity related to the pharmacological mode of action of rivaroxaban (e.g. haemorrhagic
34
complications). Embryo-foetal toxicity (post-implantation loss, retarded/progressed ossification,
hepatic multiple light coloured spots) and an increased incidence of common malformations as well as
placental changes were observed at clinically relevant plasma concentrations. In the pre- and post-
natal study in rats, reduced viability of the offspring was observed at doses that were toxic to the dams.
6. PHARMACEUTICAL PARTICULARS
Tablet core:
Microcrystalline cellulose
Croscarmellose sodium
Lactose monohydrate
Hypromellose
Sodium laurilsulfate
Magnesium stearate
Film-coat:
Macrogol 3350
Hypromellose
Titanium dioxide (E171)
Iron oxide red (E172)
6.2 Incompatibilities
Not applicable.
3 years
This medicinal product does not require any special storage conditions.
Bayer Pharma AG
13342 Berlin
Germany
35
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/08/472/001-010, EU/1/08/472/022.
{MM/YYYY}
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu.
36
This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
See section 4.8 for how to report adverse reactions.
3. PHARMACEUTICAL FORM
4. CLINICAL PARTICULARS
Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with
one or more risk factors, such as congestive heart failure, hypertension, age 75 years, diabetes
mellitus, prior stroke or transient ischaemic attack.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent
DVT and PE in adults. (See section 4.4 for haemodynamically unstable PE patients.)
Posology
Prevention of stroke and systemic embolism
The recommended dose is 20 mg once daily, which is also the recommended maximum dose.
Therapy with Xarelto should be continued long term provided the benefit of prevention of stroke and
systemic embolism outweighs the risk of bleeding (see section 4.4).
If a dose is missed the patient should take Xarelto immediately and continue on the following day with
the once daily intake as recommended. The dose should not be doubled within the same day to make
up for a missed dose.
37
Dosing schedule Maximum daily dose
Day 1 21 15 mg twice daily 30 mg
Day 22 and onwards 20 mg once daily 20 mg
To support the dose switch from 15 mg to 20 mg after Day 21 a first 4 weeks treatment initiation pack
of Xarelto for treatment of DVT/PE is available (see section 6.5).
The duration of therapy should be individualised after careful assessment of the treatment benefit
against the risk for bleeding (see section 4.4). Short duration of therapy (at least 3 months) should be
based on transient risk factors (e.g. recent surgery, trauma, immobilisation) and longer durations
should be based on permanent risk factors or idiopathic DVT or PE.
If a dose is missed during the 15 mg twice daily treatment phase (day 1 - 21), the patient should take
Xarelto immediately to ensure intake of 30 mg Xarelto per day. In this case two 15 mg tablets may be
taken at once. The patient should continue with the regular 15 mg twice daily intake as recommended
on the following day.
If a dose is missed during the once daily treatment phase (day 22 and onwards), the patient should take
Xarelto immediately, and continue on the following day with the once daily intake as recommended.
The dose should not be doubled within the same day to make up for a missed dose.
Special populations
Renal impairment
Limited clinical data for patients with severe renal impairment (creatinine clearance 15 - 29 ml/min)
indicate that rivaroxaban plasma concentrations are significantly increased. Therefore, Xarelto is to be
used with caution in these patients. Use is not recommended in patients with creatinine clearance
< 15 ml/min (see sections 4.4 and 5.2).
38
In patients with moderate (creatinine clearance 30 - 49 ml/min) or severe (creatinine clearance
15 - 29 ml/min) renal impairment the following dosage recommendations apply:
- For the prevention of stroke and systemic embolism in patients with non-valvular atrial
fibrillation, the recommended dose is 15 mg once daily (see section 5.2).
- For the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE: Patients
should be treated with 15 mg twice daily for the first 3 weeks.
Thereafter, the recommended dose is 20 mg once daily. A reduction of the dose from 20 mg
once daily to 15 mg once daily should be considered if the patients assessed risk for bleeding
outweighs the risk for recurrent DVT and PE. The recommendation for the use of 15 mg is
based on PK modelling and has not been studied in this clinical setting (see sections 4.4, 5.1 and
5.2).
No dose adjustment is necessary in patients with mild renal impairment (creatinine clearance
50 - 80 ml/min) (see section 5.2).
Hepatic impairment
Xarelto is contraindicated in patients with hepatic disease associated with coagulopathy and clinically
relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see sections 4.3 and 5.2).
Elderly population
No dose adjustment (see section 5.2).
Body weight
No dose adjustment (see section 5.2).
Gender
No dose adjustment (see section 5.2).
Paediatric population
The safety and efficacy of Xarelto in children aged 0 to 18 years have not been established. No data
are available. Therefore, Xarelto is not recommended for use in children below 18 years of age.
Method of administration
For oral use.
The tablets are to be taken with food (see section 5.2).
For patients who are unable to swallow whole tablets, Xarelto tablet may be crushed and mixed with
water or apple puree immediately prior to use and administered orally. After the administration of
crushed Xarelto 15 mg or 20 mg film-coated tablets, the dose should be immediately followed by
food.
The crushed Xarelto tablet may also be given through gastric tubes after confirmation of the correct
gastric placement of the tube. The crushed tablet should be administered in a small amount of water
via a gastric tube after which it should be flushed with water. After the administration of crushed
Xarelto15 mg or 20 mg film-coated tablets, the dose should then be immediately followed by enteral
feeding (see section 5.2).
39
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Lesion or condition, if considered to be a significant risk for major bleeding. This may include current
or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent
brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage,
known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major
intraspinal or intracerebral vascular abnormalities.
Concomitant treatment with any other anticoagulants e.g. unfractionated heparin (UFH), low
molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral
anticoagulants (warfarin, dabigatran etexilate, apixaban, etc.) except under specific circumstances of
switching anticoagulant therapy (see section 4.2) or when UFH is given at doses necessary to maintain
an open central venous or arterial catheter (see section 4.5).
Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic
patients with Child Pugh B and C (see section 5.2).
Clinical surveillance in line with anticoagulation practice is recommended throughout the treatment
period.
Haemorrhagic risk
As with other anticoagulants, patients taking Xarelto are to be carefully observed for signs of bleeding.
It is recommended to be used with caution in conditions with increased risk of haemorrhage. Xarelto
administration should be discontinued if severe haemorrhage occurs.
In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary) and
anaemia were seen more frequently during long term rivaroxaban treatment compared with VKA
treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of
haemoglobin/haematocrit could be of value to detect occult bleeding, as judged to be appropriate.
Several sub-groups of patients, as detailed below, are at increased risk of bleeding. These patients are
to be carefully monitored for signs and symptoms of bleeding complications and anaemia after
initiation of treatment (see section 4.8).
Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site.
Although treatment with rivaroxaban does not require routine monitoring of exposure, rivaroxaban
levels measured with a calibrated quantitative anti-factor Xa assay may be useful in exceptional
situations where knowledge of rivaroxaban exposure may help to inform clinical decisions, e.g.,
overdose and emergency surgery (see sections 5.1 and 5.2).
Renal impairment
In patients with severe renal impairment (creatinine clearance < 30 ml/min) rivaroxaban plasma levels
may be significantly increased (1.6 fold on average) which may lead to an increased bleeding risk.
Xarelto is to be used with caution in patients with creatinine clearance 15 - 29 ml/min. Use is not
recommended in patients with creatinine clearance < 15 ml/min (see sections 4.2 and 5.2).
Xarelto should be used with caution in patients with renal impairment concomitantly receiving other
medicinal products which increase rivaroxaban plasma concentrations (see section 4.5).
40
Interaction with other medicinal products
The use of Xarelto is not recommended in patients receiving concomitant systemic treatment with
azole-antimycotics (such as ketoconazole, itraconazole, voriconazole and posaconazole) or HIV
protease inhibitors (e.g. ritonavir). These active substances are strong inhibitors of both CYP3A4 and
P-gp and therefore may increase rivaroxaban plasma concentrations to a clinically relevant degree
(2.6 fold on average) which may lead to an increased bleeding risk (see section 4.5).
Care is to be taken if patients are treated concomitantly with medicinal products affecting haemostasis
such as non-steroidal anti-inflammatory medicinal products (NSAIDs), acetylsalicylic acid and
platelet aggregation inhibitors. For patients at risk of ulcerative gastrointestinal disease an appropriate
prophylactic treatment may be considered (see section 4.5).
41
If traumatic puncture occurs the administration of rivaroxaban is to be delayed for 24 hours.
Dosing recommendations before and after invasive procedures and surgical intervention
If an invasive procedure or surgical intervention is required, Xarelto 15 mg should be stopped at least
24 hours before the intervention, if possible and based on the clinical judgement of the physician.
If the procedure cannot be delayed the increased risk of bleeding should be assessed against the
urgency of the intervention.
Xarelto should be restarted as soon as possible after the invasive procedure or surgical intervention
provided the clinical situation allows and adequate haemostasis has been established as determined by
the treating physician (see section 5.2).
Elderly population
Increasing age may increase haemorrhagic risk (see section 5.2).
4.5 Interaction with other medicinal products and other forms of interaction
Active substances strongly inhibiting only one of the rivaroxaban elimination pathways, either
CYP3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent.
Clarithromycin (500 mg twice a day), for instance, considered as a strong CYP3A4 inhibitor and
moderate P-gp inhibitor, led to a 1.5 fold increase in mean rivaroxaban AUC and a 1.4 fold increase in
Cmax. This increase is not considered clinically relevant. (For patients with renal impairment: see
section 4.4).
Erythromycin (500 mg three times a day), which inhibits CYP3A4 and P-gp moderately, led to a
1.3 fold increase in mean rivaroxaban AUC and Cmax. This increase is not considered clinically
relevant.
In subjects with mild renal impairment erythromycin (500 mg three times a day) led to a 1.8 fold
increase in mean rivaroxaban AUC and 1.6 fold increase in C max when compared to subjects with
R
normal renal function. In subjects with moderate renal impairment, erythromycin led to a 2.0 fold
increase in mean rivaroxaban AUC and 1.6 fold increase in C max when compared to subjects with
R
normal renal function. The effect of erythromycin is additive to that of renal impairment (see section
4.4).
Fluconazole (400 mg once daily), considered as a moderate CYP3A4 inhibitor, led to a 1.4 fold
increase in mean rivaroxaban AUC and a 1.3 fold increase in mean Cmax. This increase is not
considered clinically relevant. (For patients with renal impairment: see section 4.4).
Given the limited clinical data available with dronedarone, co-administration with rivaroxaban should
be avoided.
Anticoagulants
After combined administration of enoxaparin (40 mg single dose) with rivaroxaban (10 mg single
dose) an additive effect on anti-factor Xa activity was observed without any additional effects on
clotting tests (PT, aPTT). Enoxaparin did not affect the pharmacokinetics of rivaroxaban.
42
Due to the increased bleeding risk care is to be taken if patients are treated concomitantly with any
other anticoagulants (see sections 4.3 and 4.4).
Warfarin
Converting patients from the vitamin K antagonist warfarin (INR 2.0 to 3.0) to rivaroxaban (20 mg) or
from rivaroxaban (20 mg) to warfarin (INR 2.0 to 3.0) increased prothrombin time/INR (Neoplastin)
more than additively (individual INR values up to 12 may be observed), whereas effects on aPTT,
inhibition of factor Xa activity and endogenous thrombin potential were additive.
If it is desired to test the pharmacodynamic effects of rivaroxaban during the conversion period, anti-
factor Xa activity, PiCT, and Heptest can be used as these tests were not affected by warfarin. On the
fourth day after the last dose of warfarin, all tests (including PT, aPTT, inhibition of factor Xa activity
and ETP) reflected only the effect of rivaroxaban.
If it is desired to test the pharmacodynamic effects of warfarin during the conversion period, INR
measurement can be used at the Ctrough of rivaroxaban (24 hours after the previous intake of
rivaroxaban) as this test is minimally affected by rivaroxaban at this time point.
No pharmacokinetic interaction was observed between warfarin and rivaroxaban.
CYP3A4 inducers
Co-administration of rivaroxaban with the strong CYP3A4 inducer rifampicin led to an approximate
50 % decrease in mean rivaroxaban AUC, with parallel decreases in its pharmacodynamic effects. The
concomitant use of rivaroxaban with other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine,
phenobarbital or St. Johns Wort (Hypericum perforatum)) may also lead to reduced rivaroxaban
plasma concentrations. Therefore, concomitant administration of strong CYP3A4 inducers should be
avoided unless the patient is closely observed for signs and symptoms of thrombosis.
Laboratory parameters
Clotting parameters (e.g. PT, aPTT, HepTest) are affected as expected by the mode of action of
rivaroxaban (see section 5.1).
Pregnancy
Safety and efficacy of Xarelto have not been established in pregnant women. Studies in animals have
shown reproductive toxicity (see section 5.3). Due to the potential reproductive toxicity, the intrinsic
risk of bleeding and the evidence that rivaroxaban passes the placenta, Xarelto is contraindicated
during pregnancy (see section 4.3).
Women of child-bearing potential should avoid becoming pregnant during treatment with rivaroxaban.
43
Breast feeding
Safety and efficacy of Xarelto have not been established in breast feeding women. Data from animals
indicate that rivaroxaban is secreted into milk. Therefore Xarelto is contraindicated during breast
feeding (see section 4.3). A decision must be made whether to discontinue breast feeding or to
discontinue/abstain from therapy.
Fertility
No specific studies with rivaroxaban in humans have been conducted to evaluate effects on fertility. In
a study on male and female fertility in rats no effects were seen (see section 5.3).
Xarelto has minor influence on the ability to drive and use machines. Adverse reactions like syncope
(frequency: uncommon) and dizziness (frequency: common) have been reported (see section 4.8).
Patients experiencing these adverse reactions should not drive or use machines.
Table 1: Number of patients studied, maximum daily dose and treatment duration in phase III
studies
Indication Number Maximum daily Maximum
of dose treatment duration
patients*
Prevention of venous thromboembolism 6,097 10 mg 39 days
(VTE) in adult patients undergoing
elective hip or knee replacement surgery
Prevention of venous thromboembolism 3,997 10 mg 39 days
in medically ill patients
Treatment of DVT, PE and prevention 4,556 Day 1 - 21: 30 mg 21 months
of recurrence Day 22 and onwards:
20 mg
Prevention of stroke and systemic 7,750 20 mg 41 months
embolism in patients with non-valvular
atrial fibrillation
Prevention of atherothrombotic events in 10,225 5 mg or 10 mg 31 months
patients after an ACS respectively, co-
administered with
either ASA or ASA
plus clopidogrel or
ticlopidine
*Patients exposed to at least one dose of rivaroxaban
The most commonly reported adverse reactions in patients receiving rivaroxaban were bleedings (see
section 4.4. and Description of selected adverse reactions below). The most commonly reported
bleedings (4 %) were epistaxis (5.9 %) and gastrointestinal tract haemorrhage (4.2 %).
In total about 67% of patients exposed to at least one dose of rivaroxaban were reported with treatment
emergent adverse events. About 22% of the patients experienced adverse events considered related to
treatment as assessed by investigators. In patients treated with 10 mg Xarelto undergoing hip or knee
replacement surgery and in hospitalised medically ill patients, bleeding events occurred in
approximately 6.8% and 12.6% of patients, respectively, and anaemia occurred in approximately 5.9%
and 2.1% of patients, respectively. In patients treated with either 15 mg twice daily Xarelto followed
by 20 mg once daily for treatment of DVT or PE, or with 20 mg once daily for prevention of recurrent
44
DVT and PE, bleeding events occurred in approximately 27.8% of patients and anaemia occurred in
approximately 2.2% of patients. In patients treated for prevention of stroke and systemic embolism,
bleeding of any type or severity was reported with an event rate of 28 per 100 patient years, and
anaemia with an event rate of 2.5 per 100 patient years. In patients treated for prevention of
cardiovascular death and myocardial infarction after an acute coronary syndrome (ACS), bleeding of
any type or severity was reported with an event rate of 22 per 100 patient years. Anaemia was reported
with an event rate of 1.4 per 100 patient years.
Table 2: All treatment-emergent adverse reactions reported in patients in phase III studies
Common Uncommon Rare Not known
45
Common Uncommon Rare Not known
46
Common Uncommon Rare Not known
Post-marketing observations
The following adverse reactions have been reported post-marketing in temporal association with the
use of Xarelto. The frequency of these adverse reactions reported from post-marketing experience
cannot be estimated.
Immune system disorders: Angioedema and allergic oedema (In the pooled phase III trials, these
events were uncommon ( 1/1,000 to < 1/100)).
Hepatobiliary disorders: Cholestasis, Hepatitis (incl. hepatocellular injury) (In the pooled phase III
trials, these events were rare ( 1/10,000 to < 1/1,000)).
Blood and lymphatic system disorders: Thrombocytopenia (In the pooled phase III trials, these events
were uncommon ( 1/1,000 to < 1/100)).
47
4.9 Overdose
Rare cases of overdose up to 600 mg have been reported without bleeding complications or other
adverse reactions. Due to limited absorption a ceiling effect with no further increase in average plasma
exposure is expected at supratherapeutic doses of 50 mg rivaroxaban or above.
A specific antidote antagonising the pharmacodynamic effect of rivaroxaban is not available.
The use of activated charcoal to reduce absorption in case of rivaroxaban overdose may be considered.
Management of bleeding
Should a bleeding complication arise in a patient receiving rivaroxaban, the next rivaroxaban
administration should be delayed or treatment should be discontinued as appropriate. Rivaroxaban has
a half-life of approximately 5 to 13 hours (see section 5.2). Management should be individualised
according to the severity and location of the haemorrhage. Appropriate symptomatic treatment could
be used as needed, such as mechanical compression (e.g. for severe epistaxis), surgical haemostasis
with bleeding control procedures, fluid replacement and haemodynamic support, blood products
(packed red cells or fresh frozen plasma, depending on associated anaemia or coagulopathy) or
platelets.
If bleeding cannot be controlled by the above measures, administration of a specific procoagulant
reversal agent should be considered, such as prothrombin complex concentrate (PCC), activated
prothrombin complex concentrate (APCC) or recombinant factor VIIa (r-FVIIa). However, there is
currently very limited clinical experience with the use of these products in individuals receiving
rivaroxaban. The recommendation is also based on limited non-clinical data. Re-dosing of
recombinant factor VIIa shall be considered and titrated depending on improvement of bleeding.
Depending on local availability, a consultation with a coagulation expert should be considered in case
of major bleedings (see section 5.1).
Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban.
There is limited experience with tranexamic acid and no experience with aminocaproic acid and
aprotinin in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor
experience with the use of the systemic haemostatic desmopressin in individuals receiving
rivaroxaban. Due to the high plasma protein binding rivaroxaban is not expected to be dialysable.
5. PHARMACOLOGICAL PROPERTIES
Mechanism of action
Rivaroxaban is a highly selective direct factor Xa inhibitor with oral bioavailability. Inhibition of
factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting
both thrombin formation and development of thrombi. Rivaroxaban does not inhibit thrombin
(activated Factor II) and no effects on platelets have been demonstrated.
Pharmacodynamic effects
Dose-dependent inhibition of factor Xa activity was observed in humans. Prothrombin time (PT) is
influenced by rivaroxaban in a dose dependent way with a close correlation to plasma concentrations
(r value equals 0.98) if Neoplastin is used for the assay. Other reagents would provide different results.
The readout for PT is to be done in seconds, because the INR (International Normalised Ratio) is only
calibrated and validated for coumarins and cannot be used for any other anticoagulant.
In patients receiving rivaroxaban for treatment of DVT and PE and prevention of recurrence, the 5/95
percentiles for PT (Neoplastin) 2 - 4 hours after tablet intake (i.e. at the time of maximum effect) for
15 mg rivaroxaban twice daily ranged from 17 to 32 s and for 20 mg rivaroxaban once daily from 15
to 30 s. At trough (8 - 16 h after tablet intake) the 5/95 percentiles for 15 mg twice daily ranged from
14 to 24 s and for 20 mg once daily (18 - 30 h after tablet intake) from 13 to 20 s.
48
In patients with non-valvular atrial fibrillation receiving rivaroxaban for the prevention of stroke and
systemic embolism, the 5/95 percentiles for PT (Neoplastin) 1 - 4 hours after tablet intake (i.e. at the
time of maximum effect) in patients treated with 20 mg once daily ranged from 14 to 40 s and in
patients with moderate renal impairment treated with 15 mg once daily from 10 to 50 s. At trough
(16 - 36 h after tablet intake) the 5/95 percentiles in patients treated with 20 mg once daily ranged
from 12 to 26 s and in patients with moderate renal impairment treated with 15 mg once daily from 12
to 26 s.
In a clinical pharmacology study on the reversal of rivaroxaban pharmacodynamics in healthy adult
subjects (n=22), the effects of single doses (50 IU/kg) of two different types of PCCs, a 3-factor PCC
(Factors II, IX and X) and a 4-factor PCC (Factors II, VII, IX and X) were assessed. The 3-factor PCC
reduced mean Neoplastin PT values by approximately 1.0 second within 30 minutes, compared to
reductions of approximately 3.5 seconds observed with the 4-factor PCC. In contrast, the 3-factor PCC
had a greater and more rapid overall effect on reversing changes in endogenous thrombin generation
than the 4-factor PCC (see section 4.9).
The activated partial thromboplastin time (aPTT) and HepTest are also prolonged dose-dependently;
however, they are not recommended to assess the pharmacodynamic effect of rivaroxaban. There is no
need for monitoring of coagulation parameters during treatment with rivaroxaban in clinical routine.
However, if clinically indicated rivaroxaban levels can be measured by calibrated quantitative anti-
factor Xa tests (see section 5.2).
Xarelto was non-inferior to warfarin for the primary composite endpoint of stroke and non-CNS
systemic embolism. In the per-protocol population on treatment, stroke or systemic embolism occurred
in 188 patients on rivaroxaban (1.71% per year) and 241 on warfarin (2.16% per year) (HR 0.79;
95% CI, 0.66 0.96; P<0.001 for non-inferiority). Among all randomised patients analysed according
to ITT, primary events occurred in 269 on rivaroxaban (2.12% per year) and 306 on warfarin (2.42%
per year) (HR 0.88; 95% CI, 0.74 1.03; P<0.001 for non-inferiority; P=0.117 for superiority).
Results for secondary endpoints as tested in hierarchical order in the ITT analysis are displayed in
Table 3.
Among patients in the warfarin group, INR values were within the therapeutic range (2.0 to 3.0) a
mean of 55% of the time (median, 58%; interquartile range, 43 to 71). The effect of rivaroxaban did
not differ across the level of centre TTR (Time in Target INR Range of 2.0 - 3.0) in the equally sized
quartiles (P=0.74 for interaction). Within the highest quartile according to centre, the hazard ratio with
rivaroxaban versus warfarin was 0.74 (95% CI, 0.49 - 1.12).
The incidence rates for the principal safety outcome (major and non-major clinically relevant bleeding
events) were similar for both treatment groups (see Table 4).
49
Table 3: Efficacy results from phase III ROCKET AF
Study population ITT analyses of efficacy in patients with non-valvular atrial fibrillation
Xarelto Warfarin
20 mg od titrated to a target INR
Hazard ratio (95%
(15 mg od in patients of 2.5 (therapeutic
Treatment dosage CI)
with moderate renal range 2.0 to 3.0)
p-value, test for
impairment)
superiority
Event rate (100 pt-yr) Event rate (100 pt-yr)
Non-CNS 20 27 0.74
systemic (0.16) (0.21) (0.42 - 1.32)
embolism 0.308
50
Table 4: Safety results from phase III ROCKET AF
Study population Patients with non-valvular atrial fibrillationa)
Xarelto Warfarin
20 mg once a day titrated to a target INR of
(15 mg once a day in 2.5 (therapeutic range Hazard ratio
Treatment dosage patients with moderate 2.0 to 3.0) (95% CI)
renal impairment) p-value
In addition to the phase III ROCKET AF study, a prospective, single-arm, post-authorization, non-
interventional, open-label cohort study (XANTUS) with central outcome adjudication including
thromboembolic events and major bleeding has been conducted. 6,785 patients with non-valvular
atrial fibrillation were enrolled for prevention of stroke and non-central nervous system (CNS)
systemic embolism in clinical practice. The mean CHADS2 and HAS-BLED scores were both 2.0 in
XANTUS, compared to a mean CHADS2 and HAS-BLED score of 3.5 and 2.8 in ROCKET AF,
respectively. Major bleeding occurred in 2.1 per 100 patient years. Fatal haemorrhage was reported in
0.2 per 100 patient years and intracranial haemorrhage in 0.4 per 100 patient years. Stroke or non-CNS
systemic embolism was recorded in 0.8 per 100 patient years.
These observations in clinical practice are consistent with the established safety profile in this
indication.
In Einstein DVT 3,449 patients with acute DVT were studied for the treatment of DVT and the
prevention of recurrent DVT and PE (patients who presented with symptomatic PE were excluded
from this study). The treatment duration was for 3, 6 or 12 months depending on the clinical
judgement of the investigator.
For the initial 3 week treatment of acute DVT 15 mg rivaroxaban was administered twice daily. This
was followed by 20 mg rivaroxaban once daily.
In Einstein PE, 4,832 patients with acute PE were studied for the treatment of PE and the prevention of
recurrent DVT and PE. The treatment duration was for 3, 6 or 12 months depending on the clinical
judgement of the investigator.
For the initial treatment of acute PE 15 mg rivaroxaban was administered twice daily for three weeks.
This was followed by 20 mg rivaroxaban once daily.
In both the Einstein DVT and the Einstein PE study, the comparator treatment regimen consisted of
enoxaparin administered for at least 5 days in combination with vitamin K antagonist treatment until
the PT/INR was in therapeutic range ( 2.0). Treatment was continued with a vitamin K antagonist
dose-adjusted to maintain the PT/INR values within the therapeutic range of 2.0 to 3.0.
In Einstein Extension 1,197 patients with DVT or PE were studied for the prevention of recurrent
DVT and PE. The treatment duration was for an additional 6 or 12 months in patients who had
completed 6 to 12 months of treatment for venous thromboembolism depending on the clinical
judgment of the investigator. Xarelto 20 mg once daily was compared with placebo.
All phase III studies used the same pre-defined primary and secondary efficacy outcomes. The
primary efficacy outcome was symptomatic recurrent VTE defined as the composite of recurrent DVT
or fatal or non-fatal PE. The secondary efficacy outcome was defined as the composite of recurrent
DVT, non-fatal PE and all cause mortality.
In the Einstein DVT study (see Table 5) rivaroxaban was demonstrated to be non-inferior to
enoxaparin/VKA for the primary efficacy outcome (p < 0.0001 (test for non-inferiority); hazard ratio:
0.680 (0.443 - 1.042), p=0.076 (test for superiority)). The prespecified net clinical benefit (primary
efficacy outcome plus major bleeding events) was reported with a hazard ratio of 0.67
((95% CI: 0.47 - 0.95), nominal p value p=0.027) in favour of rivaroxaban. INR values were within
the therapeutic range a mean of 60.3% of the time for the mean treatment duration of 189 days, and
55.4%, 60.1%, and 62.8% of the time in the 3-, 6-, and 12-month intended treatment duration groups,
respectively. In the enoxaparin/VKA group, there was no clear relation between the level of mean
centre TTR (Time in Target INR Range of 2.0 3.0) in the equally sized tertiles and the incidence of
52
the recurrent VTE (P=0.932 for interaction). Within the highest tertile according to centre, the hazard
ratio with rivaroxaban versus warfarin was 0.69 (95% CI: 0.35 - 1.35).
The incidence rates for the primary safety outcome (major or clinically relevant non-major bleeding
events) as well as the secondary safety outcome (major bleeding events) were similar for both
treatment groups.
Table 5: Efficacy and safety results from phase III Einstein DVT
Study population 3,449 patients with symptomatic acute deep vein thrombosis
Xareltoa) Enoxaparin/VKAb)
Treatment dosage and duration 3, 6 or 12 months 3, 6 or 12 months
N=1,731 N=1,718
36 51
Symptomatic recurrent VTE* (2.1%) (3.0%)
20 18
Symptomatic recurrent PE
(1.2%) (1.0%)
14 28
Symptomatic recurrent DVT
(0.8%) (1.6%)
1
Symptomatic PE and DVT 0
(0.1%)
Fatal PE/Death where PE 4 6
cannot be ruled out (0.2%) (0.3%)
Major or clinically relevant non- 139 138
major bleeding (8.1%) (8.1%)
14 20
Major bleeding events
(0.8%) (1.2%)
a) Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily
b) Enoxaparin for at least 5 days, overlapped with and followed by VKA
* p < 0.0001 (non-inferiority to a prespecified hazard ratio of 2.0); hazard ratio: 0.680
(0.443 - 1.042), p=0.076 (superiority)
The incidence rates for the primary safety outcome (major or clinically relevant non-major bleeding
events) were slightly lower in the rivaroxaban treatment group (10.3% (249/2412)) than in the
enoxaparin/VKA treatment group (11.4% (274/2405)). The incidence of the secondary safety outcome
(major bleeding events) was lower in the rivaroxaban group (1.1% (26/2412)) than in the
enoxaparin/VKA group (2.2% (52/2405)) with a hazard ratio 0.493 (95% CI: 0.308 - 0.789).
53
Table 6: Efficacy and safety results from phase III Einstein PE
Study population 4,832 patients with an acute symptomatic PE
Xareltoa) Enoxaparin/VKAb)
Treatment dosage and duration 3, 6 or 12 months 3, 6 or 12 months
N=2,419 N=2,413
50 44
Symptomatic recurrent VTE* (2.1%) (1.8%)
23 20
Symptomatic recurrent PE
(1.0%) (0.8%)
18 17
Symptomatic recurrent DVT
(0.7%) (0.7%)
2
Symptomatic PE and DVT 0
(<0.1%)
Fatal PE/Death where PE 11 7
cannot be ruled out (0.5%) (0.3%)
Major or clinically relevant non- 249 274
major bleeding (10.3%) (11.4%)
26 52
Major bleeding events
(1.1%) (2.2%)
a) Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily
b) Enoxaparin for at least 5 days, overlapped with and followed by VKA
* p < 0.0026 (non-inferiority to a prespecified hazard ratio of 2.0); hazard ratio: 1.123 (0.749
1.684)
A prespecified pooled analysis of the outcome of the Einstein DVT and PE studies was conducted (see
Table 7).
Table 7: Efficacy and safety results from pooled analysis of phase III Einstein DVT and
Einstein PE
Study population 8,281 patients with an acute symptomatic DVT or PE
Xareltoa) Enoxaparin/VKAb)
Treatment dosage and duration 3, 6 or 12 months 3, 6 or 12 months
N=4,150 N=4,131
86 95
Symptomatic recurrent VTE* (2.1%) (2.3%)
43 38
Symptomatic recurrent PE
(1.0%) (0.9%)
32 45
Symptomatic recurrent DVT
(0.8%) (1.1%)
1 2
Symptomatic PE and DVT
(<0.1%) (<0.1%)
Fatal PE/Death where PE 15 13
cannot be ruled out (0.4%) (0.3%)
Major or clinically relevant non- 388 412
major bleeding (9.4%) (10.0%)
40 72
Major bleeding events
(1.0%) (1.7%)
a) Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily
b) Enoxaparin for at least 5 days, overlapped with and followed by VKA
* p < 0.0001 (non-inferiority to a prespecified hazard ratio of 1.75); hazard ratio: 0.886 (0.661
1.186)
The prespecified net clinical benefit (primary efficacy outcome plus major bleeding events) of the
pooled analysis was reported with a hazard ratio of 0.771 ((95% CI: 0.614 0.967), nominal p value
p= 0.0244).
54
In the Einstein Extension study (see Table 8) rivaroxaban was superior to placebo for the primary and
secondary efficacy outcomes. For the primary safety outcome (major bleeding events) there was a
non-significant numerically higher incidence rate for patients treated with rivaroxaban 20 mg once
daily compared to placebo. The secondary safety outcome (major or clinically relevant non-major
bleeding events) showed higher rates for patients treated with rivaroxaban 20 mg once daily compared
to placebo.
Table 8: Efficacy and safety results from phase III Einstein Extension
1,197 patients continued treatment and prevention
Study population
of recurrent venous thromboembolism
Xareltoa) Placebo
Treatment dosage and duration 6 or 12 months 6 or 12 months
N=602 N=594
8 42
Symptomatic recurrent VTE* (1.3%) (7.1%)
2 13
Symptomatic recurrent PE
(0.3%) (2.2%)
5 31
Symptomatic recurrent DVT
(0.8%) (5.2%)
Fatal PE/Death where PE 1 1
cannot be ruled out (0.2%) (0.2%)
4 0
Major bleeding events
(0.7%) (0.0%)
Clinically relevant non-major 32 7
bleeding (5.4%) (1.2%)
a) Rivaroxaban 20 mg once daily
* p < 0.0001 (superiority), hazard ratio: 0.185 (0.087 - 0.393)
In addition to the phase III EINSTEIN program, a prospective, non-interventional, open-label cohort
study (XALIA) with central outcome adjudication including recurrent VTE, major bleeding and death
has been conducted. 5,142 patients with acute DVT were enrolled to investigate the long-term safety
of rivaroxaban compared with standard-of-care anticoagulation therapy in clinical practice. Rates of
major bleeding, recurrent VTE and all-cause mortality for rivaroxaban were 0.7%, 1.4% and 0.5%,
respectively. There were differences in patient baseline characteristics including age, cancer and renal
impairment. A pre-specified propensity score stratified analysis was used to adjust for measured
baseline differences but residual confounding may, in spite of this, influence the results. Adjusted
hazard ratios comparing rivaroxaban and standard-of-care for major bleeding, recurrent VTE and all-
cause mortality were 0.77 (95% CI 0.40 - 1.50), 0.91 (95% CI 0.54 - 1.54) and 0.51 (95% CI
0.24 - 1.07), respectively.
These results in clinical practice are consistent with the established safety profile in this indication.
Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with
Xarelto in one or more subsets of the paediatric population in the treatment of thromboembolic events.
The European Medicines Agency has waived the obligation to submit the results of studies with
Xarelto in all subsets of the paediatric population in the prevention of thromboembolic events (see
section 4.2 for information on paediatric use).
Absorption
Rivaroxaban is rapidly absorbed with maximum concentrations (Cmax) appearing 2 - 4 hours after
tablet intake.
Oral absorption of rivaroxaban is almost complete and oral bioavailability is high (80 - 100%) for the
2.5 mg and 10 mg tablet dose, irrespective of fasting/fed conditions. Intake with food does not affect
rivaroxaban AUC or Cmax at the 2.5 mg and 10 mg dose.
55
Due to a reduced extent of absorption an oral bioavailability of 66% was determined for the 20 mg
tablet under fasting conditions. When Xarelto 20 mg tablets are taken together with food increases in
mean AUC by 39% were observed when compared to tablet intake under fasting conditions, indicating
almost complete absorption and high oral bioavailability. Xarelto 15 mg and 20 mg are to be taken
with food (see section 4.2).
Rivaroxaban pharmacokinetics are approximately linear up to about 15 mg once daily in fasting state.
Under fed conditions Xarelto 10 mg, 15 mg and 20 mg tablets demonstrated dose-proportionality. At
higher doses rivaroxaban displays dissolution limited absorption with decreased bioavailability and
decreased absorption rate with increased dose.
Variability in rivaroxaban pharmacokinetics is moderate with inter-individual variability (CV%)
ranging from 30% to 40%.
Absorption of rivaroxaban is dependent on the site of its release in the gastrointestinal tract. A 29%
and 56% decrease in AUC and Cmax compared to tablet was reported when rivaroxaban granulate is
released in the proximal small intestine. Exposure is further reduced when rivaroxaban is released in
the distal small intestine, or ascending colon. Therefore, administration of rivaroxaban distal to the
stomach should be avoided since this can result in reduced absorption and related rivaroxaban
exposure.
Bioavailability (AUC and Cmax) was comparable for 20 mg rivaroxaban administered orally as a
crushed tablet mixed in apple puree, or suspended in water and administered via a gastric tube
followed by a liquid meal, compared to a whole tablet. Given the predictable, dose-proportional
pharmacokinetic profile of rivaroxaban, the bioavailability results from this study are likely applicable
to lower rivaroxaban doses.
Distribution
Plasma protein binding in humans is high at approximately 92 % to 95 %, with serum albumin being
the main binding component. The volume of distribution is moderate with Vss being approximately
50 litres.
Special populations
Gender
There were no clinically relevant differences in pharmacokinetics and pharmacodynamics between
male and female patients.
Elderly population
Elderly patients exhibited higher plasma concentrations than younger patients, with mean AUC values
being approximately 1.5 fold higher, mainly due to reduced (apparent) total and renal clearance. No
dose adjustment is necessary.
56
Inter-ethnic differences
No clinically relevant inter-ethnic differences among Caucasian, African-American, Hispanic,
Japanese or Chinese patients were observed regarding rivaroxaban pharmacokinetics and
pharmacodynamics.
Hepatic impairment
Cirrhotic patients with mild hepatic impairment (classified as Child Pugh A) exhibited only minor
changes in rivaroxaban pharmacokinetics (1.2 fold increase in rivaroxaban AUC on average), nearly
comparable to their matched healthy control group. In cirrhotic patients with moderate hepatic
impairment (classified as Child Pugh B), rivaroxaban mean AUC was significantly increased by
2.3 fold compared to healthy volunteers. Unbound AUC was increased 2.6 fold. These patients also
had reduced renal elimination of rivaroxaban, similar to patients with moderate renal impairment.
There are no data in patients with severe hepatic impairment.
The inhibition of factor Xa activity was increased by a factor of 2.6 in patients with moderate hepatic
impairment as compared to healthy volunteers; prolongation of PT was similarly increased by a factor
of 2.1. Patients with moderate hepatic impairment were more sensitive to rivaroxaban resulting in a
steeper PK/PD relationship between concentration and PT.
Xarelto is contraindicated in patients with hepatic disease associated with coagulopathy and clinically
relevant bleeding risk, including cirrhotic patients with Child Pugh B and C (see section 4.3).
Renal impairment
There was an increase in rivaroxaban exposure correlated to decrease in renal function, as assessed via
creatinine clearance measurements. In individuals with mild (creatinine clearance 50 - 80 ml/min),
moderate (creatinine clearance 30 - 49 ml/min) and severe (creatinine clearance 15 - 29 ml/min) renal
impairment, rivaroxaban plasma concentrations (AUC) were increased 1.4, 1.5 and 1.6 fold
respectively. Corresponding increases in pharmacodynamic effects were more pronounced. In
individuals with mild, moderate and severe renal impairment the overall inhibition of factor Xa
activity was increased by a factor of 1.5, 1.9 and 2.0 respectively as compared to healthy volunteers;
prolongation of PT was similarly increased by a factor of 1.3, 2.2 and 2.4 respectively. There are no
data in patients with creatinine clearance < 15 ml/min.
Due to the high plasma protein binding rivaroxaban is not expected to be dialysable.
Use is not recommended in patients with creatinine clearance < 15 ml/min. Xarelto is to be used with
caution in patients with creatinine clearance 15 - 29 ml/min (see section 4.4).
Pharmacokinetic/pharmacodynamic relationship
The pharmacokinetic/pharmacodynamic (PK/PD) relationship between rivaroxaban plasma
concentration and several PD endpoints (factor Xa inhibition, PT, aPTT, Heptest) has been evaluated
after administration of a wide range of doses (5 - 30 mg twice a day). The relationship between
rivaroxaban concentration and factor Xa activity was best described by an Emax model. For PT, the
linear intercept model generally described the data better. Depending on the different PT reagents
used, the slope differed considerably. When Neoplastin PT was used, baseline PT was about 13 s and
the slope was around 3 to 4 s/(100 g/l). The results of the PK/PD analyses in Phase II and III were
consistent with the data established in healthy subjects.
Paediatric population
Safety and efficacy have not been established for children and adolescents up to 18 years.
57
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, single dose toxicity, phototoxicity, genotoxicity, carcinogenic potential and juvenile
toxicity.
Effects observed in repeat-dose toxicity studies were mainly due to the exaggerated pharmacodynamic
activity of rivaroxaban. In rats, increased IgG and IgA plasma levels were seen at clinically relevant
exposure levels.
In rats, no effects on male or female fertility were seen. Animal studies have shown reproductive
toxicity related to the pharmacological mode of action of rivaroxaban (e.g. haemorrhagic
complications). Embryo-foetal toxicity (post-implantation loss, retarded/progressed ossification,
hepatic multiple light coloured spots) and an increased incidence of common malformations as well as
placental changes were observed at clinically relevant plasma concentrations. In the pre- and post-
natal study in rats, reduced viability of the offspring was observed at doses that were toxic to the dams.
6. PHARMACEUTICAL PARTICULARS
Tablet core:
Microcrystalline cellulose
Croscarmellose sodium
Lactose monohydrate
Hypromellose
Sodium laurilsulfate
Magnesium stearate
Film-coat:
Macrogol 3350
Hypromellose
Titanium dioxide (E171)
Iron oxide red (E172)
6.2 Incompatibilities
Not applicable.
3 years
This medicinal product does not require any special storage conditions.
PP/Aluminium foil blisters in cartons of 10, 14, 28, 42 or 98 film-coated tablets or perforated unit dose
blisters in cartons of 10 x 1, or 100 x 1 or in multipacks containing 100 (10 packs of 10 x 1) film-
coated tablets.
HDPE bottles of 100 film-coated tablets with a PP screw cap.
PP/Aluminium foil blisters in a wallet containing 42 film-coated tablets Xarelto 15 mg and 7 film-
coated tablets Xarelto 20 mg (treatment initiation pack).
58
6.6 Special precautions for disposal
Bayer Pharma AG
13342 Berlin
Germany
{MM/YYYY}
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu.
59
This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
See section 4.8 for how to report adverse reactions.
3. PHARMACEUTICAL FORM
4. CLINICAL PARTICULARS
Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with
one or more risk factors, such as congestive heart failure, hypertension, age 75 years, diabetes
mellitus, prior stroke or transient ischaemic attack.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent
DVT and PE in adults. (See section 4.4 for haemodynamically unstable PE patients.)
Posology
Prevention of stroke and systemic embolism
The recommended dose is 20 mg once daily, which is also the recommended maximum dose.
Therapy with Xarelto should be continued long term provided the benefit of prevention of stroke and
systemic embolism outweighs the risk of bleeding (see section 4.4).
If a dose is missed the patient should take Xarelto immediately and continue on the following day with
the once daily intake as recommended. The dose should not be doubled within the same day to make
up for a missed dose.
60
Dosing schedule Maximum daily dose
Day 1 - 21 15 mg twice daily 30 mg
Day 22 and onwards 20 mg once daily 20 mg
To support the dose switch from 15 mg to 20 mg after Day 21 a first 4 weeks treatment initiation pack
of Xarelto for treatment of DVT/PE is available (see section 6.5).
The duration of therapy should be individualised after careful assessment of the treatment benefit
against the risk for bleeding (see section 4.4). Short duration of therapy (at least 3 months) should be
based on transient risk factors (e.g. recent surgery, trauma, immobilisation) and longer durations
should be based on permanent risk factors or idiopathic DVT or PE.
If a dose is missed during the 15 mg twice daily treatment phase (day 1 - 21), the patient should take
Xarelto immediately to ensure intake of 30 mg Xarelto per day. In this case two 15 mg tablets may be
taken at once. The patient should continue with the regular 15 mg twice daily intake as recommended
on the following day.
If a dose is missed during the once daily treatment phase (day 22 and onwards), the patient should take
Xarelto immediately, and continue on the following day with the once daily intake as recommended.
The dose should not be doubled within the same day to make up for a missed dose.
Special populations
Renal impairment
Limited clinical data for patients with severe renal impairment (creatinine clearance 15 - 29 ml/min)
indicate that rivaroxaban plasma concentrations are significantly increased. Therefore, Xarelto is to be
used with caution in these patients. Use is not recommended in patients with creatinine clearance
< 15 ml/min (see sections 4.4 and 5.2).
61
In patients with moderate (creatinine clearance 30 - 49 ml/min) or severe (creatinine clearance
15 - 29 ml/min) renal impairment the following dosage recommendations apply:
- For the prevention of stroke and systemic embolism in patients with non-valvular atrial
fibrillation, the recommended dose is 15 mg once daily (see section 5.2).
- For the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE: Patients
should be treated with 15 mg twice daily for the first 3 weeks.
Thereafter, the recommended dose is 20 mg once daily. A reduction of the dose from 20 mg
once daily to 15 mg once daily should be considered if the patients assessed risk for bleeding
outweighs the risk for recurrent DVT and PE. The recommendation for the use of 15 mg is
based on PK modelling and has not been studied in this clinical setting (see sections 4.4, 5.1 and
5.2).
No dose adjustment is necessary in patients with mild renal impairment (creatinine clearance
50 - 80 ml/min) (see section 5.2).
Hepatic impairment
Xarelto is contraindicated in patients with hepatic disease associated with coagulopathy and clinically
relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see sections 4.3 and 5.2).
Elderly population
No dose adjustment (see section 5.2).
Body weight
No dose adjustment (see section 5.2).
Gender
No dose adjustment (see section 5.2).
Paediatric population
The safety and efficacy of Xarelto in children aged 0 to 18 years have not been established. No data
are available. Therefore, Xarelto is not recommended for use in children below 18 years of age.
Method of administration
For oral use.
The tablets are to be taken with food (see section 5.2).
For patients who are unable to swallow whole tablets, Xarelto tablet may be crushed and mixed with
water or apple puree immediately prior to use and administered orally. After the administration of
crushed Xarelto 15 mg or 20 mg film-coated tablets, the dose should be immediately followed by
food.
The crushed Xarelto tablet may also be given through gastric tubes after confirmation of the correct
gastric placement of the tube. The crushed tablet should be administered in a small amount of water
via a gastric tube after which it should be flushed with water. After the administration of crushed
Xarelto15 mg or 20 mg film-coated tablets, the dose should then be immediately followed by enteral
feeding (see section 5.2).
62
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Lesion or condition, if considered to be a significant risk for major bleeding. This may include current
or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent
brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage,
known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major
intraspinal or intracerebral vascular abnormalities.
Concomitant treatment with any other anticoagulants e.g. unfractionated heparin (UFH), low
molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral
anticoagulants (warfarin, dabigatran etexilate, apixaban, etc.) except under specific circumstances of
switching anticoagulant therapy (see section 4.2) or when UFH is given at doses necessary to maintain
an open central venous or arterial catheter (see section 4.5).
Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic
patients with Child Pugh B and C (see section 5.2).
Clinical surveillance in line with anticoagulation practice is recommended throughout the treatment
period.
Haemorrhagic risk
As with other anticoagulants, patients taking Xarelto are to be carefully observed for signs of bleeding.
It is recommended to be used with caution in conditions with increased risk of haemorrhage. Xarelto
administration should be discontinued if severe haemorrhage occurs.
In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary) and
anaemia were seen more frequently during long term rivaroxaban treatment compared with VKA
treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of
haemoglobin/haematocrit could be of value to detect occult bleeding, as judged to be appropriate.
Several sub-groups of patients, as detailed below, are at increased risk of bleeding. These patients are
to be carefully monitored for signs and symptoms of bleeding complications and anaemia after
initiation of treatment (see section 4.8).
Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site.
Although treatment with rivaroxaban does not require routine monitoring of exposure, rivaroxaban
levels measured with a calibrated quantitative anti-factor Xa assay may be useful in exceptional
situations where knowledge of rivaroxaban exposure may help to inform clinical decisions, e.g.,
overdose and emergency surgery (see sections 5.1 and 5.2).
Renal impairment
In patients with severe renal impairment (creatinine clearance < 30 ml/min) rivaroxaban plasma levels
may be significantly increased (1.6 fold on average) which may lead to an increased bleeding risk.
Xarelto is to be used with caution in patients with creatinine clearance 15 - 29 ml/min. Use is not
recommended in patients with creatinine clearance < 15 ml/min (see sections 4.2 and 5.2).
Xarelto should be used with caution in patients with renal impairment concomitantly receiving other
medicinal products which increase rivaroxaban plasma concentrations (see section 4.5).
63
Interaction with other medicinal products
The use of Xarelto is not recommended in patients receiving concomitant systemic treatment with
azole-antimycotics (such as ketoconazole, itraconazole, voriconazole and posaconazole) or HIV
protease inhibitors (e.g. ritonavir). These active substances are strong inhibitors of both CYP3A4 and
P-gp and therefore may increase rivaroxaban plasma concentrations to a clinically relevant degree
(2.6 fold on average) which may lead to an increased bleeding risk (see section 4.5).
Care is to be taken if patients are treated concomitantly with medicinal products affecting haemostasis
such as non-steroidal anti-inflammatory medicinal products (NSAIDs), acetylsalicylic acid and
platelet aggregation inhibitors. For patients at risk of ulcerative gastrointestinal disease an appropriate
prophylactic treatment may be considered (see section 4.5).
64
If traumatic puncture occurs the administration of rivaroxaban is to be delayed for 24 hours.
Dosing recommendations before and after invasive procedures and surgical intervention
If an invasive procedure or surgical intervention is required, Xarelto 20 mg should be stopped at least
24 hours before the intervention, if possible and based on the clinical judgement of the physician.
If the procedure cannot be delayed the increased risk of bleeding should be assessed against the
urgency of the intervention.
Xarelto should be restarted as soon as possible after the invasive procedure or surgical intervention
provided the clinical situation allows and adequate haemostasis has been established as determined by
the treating physician (see section 5.2).
Elderly population
Increasing age may increase haemorrhagic risk (see section 5.2).
4.5 Interaction with other medicinal products and other forms of interaction
Active substances strongly inhibiting only one of the rivaroxaban elimination pathways, either
CYP3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent.
Clarithromycin (500 mg twice a day), for instance, considered as a strong CYP3A4 inhibitor and
moderate P-gp inhibitor, led to a 1.5 fold increase in mean rivaroxaban AUC and a 1.4 fold increase in
Cmax. This increase is not considered clinically relevant. (For patients with renal impairment: see
section 4.4).
Erythromycin (500 mg three times a day), which inhibits CYP3A4 and P-gp moderately, led to a
1.3 fold increase in mean rivaroxaban AUC and Cmax. This increase is not considered clinically
relevant.
In subjects with mild renal impairment erythromycin (500 mg three times a day) led to a 1.8 fold
increase in mean rivaroxaban AUC and 1.6 fold increase in C max when compared to subjects with
R
normal renal function. In subjects with moderate renal impairment, erythromycin led to a 2.0 fold
increase in mean rivaroxaban AUC and 1.6 fold increase in C max when compared to subjects with
R
normal renal function. The effect of erythromycin is additive to that of renal impairment (see section
4.4).
Fluconazole (400 mg once daily), considered as a moderate CYP3A4 inhibitor, led to a 1.4 fold
increase in mean rivaroxaban AUC and a 1.3 fold increase in mean Cmax. This increase is not
considered clinically relevant. (For patients with renal impairment: see section 4.4).
Given the limited clinical data available with dronedarone, co-administration with rivaroxaban should
be avoided.
Anticoagulants
After combined administration of enoxaparin (40 mg single dose) with rivaroxaban (10 mg single
dose) an additive effect on anti-factor Xa activity was observed without any additional effects on
clotting tests (PT, aPTT). Enoxaparin did not affect the pharmacokinetics of rivaroxaban.
65
Due to the increased bleeding risk care is to be taken if patients are treated concomitantly with any
other anticoagulants (see sections 4.3 and 4.4).
Warfarin
Converting patients from the vitamin K antagonist warfarin (INR 2.0 to 3.0) to rivaroxaban (20 mg) or
from rivaroxaban (20 mg) to warfarin (INR 2.0 to 3.0) increased prothrombin time/INR (Neoplastin)
more than additively (individual INR values up to 12 may be observed), whereas effects on aPTT,
inhibition of factor Xa activity and endogenous thrombin potential were additive.
If it is desired to test the pharmacodynamic effects of rivaroxaban during the conversion period, anti-
factor Xa activity, PiCT, and Heptest can be used as these tests were not affected by warfarin. On the
fourth day after the last dose of warfarin, all tests (including PT, aPTT, inhibition of factor Xa activity
and ETP) reflected only the effect of rivaroxaban.
If it is desired to test the pharmacodynamic effects of warfarin during the conversion period, INR
measurement can be used at the Ctrough of rivaroxaban (24 hours after the previous intake of
rivaroxaban) as this test is minimally affected by rivaroxaban at this time point.
No pharmacokinetic interaction was observed between warfarin and rivaroxaban.
CYP3A4 inducers
Co-administration of rivaroxaban with the strong CYP3A4 inducer rifampicin led to an approximate
50 % decrease in mean rivaroxaban AUC, with parallel decreases in its pharmacodynamic effects. The
concomitant use of rivaroxaban with other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine,
phenobarbital or St. Johns Wort (Hypericum perforatum)) may also lead to reduced rivaroxaban
plasma concentrations. Therefore, concomitant administration of strong CYP3A4 inducers should be
avoided unless the patient is closely observed for signs and symptoms of thrombosis.
Laboratory parameters
Clotting parameters (e.g. PT, aPTT, HepTest) are affected as expected by the mode of action of
rivaroxaban (see section 5.1).
Pregnancy
Safety and efficacy of Xarelto have not been established in pregnant women. Studies in animals have
shown reproductive toxicity (see section 5.3). Due to the potential reproductive toxicity, the intrinsic
risk of bleeding and the evidence that rivaroxaban passes the placenta, Xarelto is contraindicated
during pregnancy (see section 4.3).
Women of child-bearing potential should avoid becoming pregnant during treatment with rivaroxaban.
66
Breast feeding
Safety and efficacy of Xarelto have not been established in breast feeding women. Data from animals
indicate that rivaroxaban is secreted into milk. Therefore Xarelto is contraindicated during breast
feeding (see section 4.3). A decision must be made whether to discontinue breast feeding or to
discontinue/abstain from therapy.
Fertility
No specific studies with rivaroxaban in humans have been conducted to evaluate effects on fertility. In
a study on male and female fertility in rats no effects were seen (see section 5.3).
Xarelto has minor influence on the ability to drive and use machines. Adverse reactions like syncope
(frequency: uncommon) and dizziness (frequency: common) have been reported (see section 4.8).
Patients experiencing these adverse reactions should not drive or use machines.
Table 1: Number of patients studied, maximum daily dose and treatment duration in phase III
studies
Indication Number Maximum daily Maximum
of dose treatment duration
patients*
Prevention of venous thromboembolism 6,097 10 mg 39 days
(VTE) in adult patients undergoing
elective hip or knee replacement surgery
Prevention of venous thromboembolism 3,997 10 mg 39 days
in medically ill patients
Treatment of DVT, PE and prevention 4,556 Day 1 - 21: 30 mg 21 months
of recurrence Day 22 and onwards:
20 mg
Prevention of stroke and systemic 7,750 20 mg 41 months
embolism in patients with non-valvular
atrial fibrillation
Prevention of atherothrombotic events in 10,225 5 mg or 10 mg 31 months
patients after an ACS respectively, co-
administered with
either ASA or ASA
plus clopidogrel or
ticlopidine
*Patients exposed to at least one dose of rivaroxaban
The most commonly reported adverse reactions in patients receiving rivaroxaban were bleedings (see
section 4.4. and Description of selected adverse reactions below). The most commonly reported
bleedings (4 %) were epistaxis (5.9 %) and gastrointestinal tract haemorrhage (4.2 %).
In total about 67% of patients exposed to at least one dose of rivaroxaban were reported with treatment
emergent adverse events. About 22% of the patients experienced adverse events considered related to
treatment as assessed by investigators. In patients treated with 10 mg Xarelto undergoing hip or knee
replacement surgery and in hospitalised medically ill patients, bleeding events occurred in
approximately 6.8% and 12.6% of patients, respectively, and anaemia occurred in approximately 5.9%
and 2.1% of patients, respectively. In patients treated with either 15 mg twice daily Xarelto followed
by 20 mg once daily for treatment of DVT or PE, or with 20 mg once daily for prevention of recurrent
67
DVT and PE, bleeding events occurred in approximately 27.8% of patients and anaemia occurred in
approximately 2.2% of patients. In patients treated for prevention of stroke and systemic embolism,
bleeding of any type or severity was reported with an event rate of 28 per 100 patient years, and
anaemia with an event rate of 2.5 per 100 patient years. In patients treated for prevention of
cardiovascular death and myocardial infarction after an acute coronary syndrome (ACS), bleeding of
any type or severity was reported with an event rate of 22 per 100 patient years. Anaemia was reported
with an event rate of 1.4 per 100 patient years.
Table 2: All treatment-emergent adverse reactions reported in patients in phase III studies
Common Uncommon Rare Not known
68
Common Uncommon Rare Not known
69
Common Uncommon Rare Not known
Post-marketing observations
The following adverse reactions have been reported post-marketing in temporal association with the
use of Xarelto. The frequency of these adverse reactions reported from post-marketing experience
cannot be estimated.
Immune system disorders: Angioedema and allergic oedema (In the pooled phase III trials, these
events were uncommon ( 1/1,000 to < 1/100)).
Hepatobiliary disorders: Cholestasis, Hepatitis (incl. hepatocellular injury) (In the pooled phase III
trials, these events were rare ( 1/10,000 to < 1/1,000)).
Blood and lymphatic system disorders: Thrombocytopenia (In the pooled phase III trials, these events
were uncommon ( 1/1,000 to < 1/100)).
70
4.9 Overdose
Rare cases of overdose up to 600 mg have been reported without bleeding complications or other
adverse reactions. Due to limited absorption a ceiling effect with no further increase in average plasma
exposure is expected at supratherapeutic doses of 50 mg rivaroxaban or above.
A specific antidote antagonising the pharmacodynamic effect of rivaroxaban is not available.
The use of activated charcoal to reduce absorption in case of rivaroxaban overdose may be considered.
Management of bleeding
Should a bleeding complication arise in a patient receiving rivaroxaban, the next rivaroxaban
administration should be delayed or treatment should be discontinued as appropriate. Rivaroxaban has
a half-life of approximately 5 to 13 hours (see section 5.2). Management should be individualised
according to the severity and location of the haemorrhage. Appropriate symptomatic treatment could
be used as needed, such as mechanical compression (e.g. for severe epistaxis), surgical haemostasis
with bleeding control procedures, fluid replacement and haemodynamic support, blood products
(packed red cells or fresh frozen plasma, depending on associated anaemia or coagulopathy) or
platelets.
If bleeding cannot be controlled by the above measures, administration of a specific procoagulant
reversal agent should be considered, such as prothrombin complex concentrate (PCC), activated
prothrombin complex concentrate (APCC) or recombinant factor VIIa (r-FVIIa). However, there is
currently very limited clinical experience with the use of these products in individuals receiving
rivaroxaban. The recommendation is also based on limited non-clinical data. Re-dosing of
recombinant factor VIIa shall be considered and titrated depending on improvement of bleeding.
Depending on local availability, a consultation with a coagulation expert should be considered in case
of major bleedings (see section 5.1).
Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban.
There is limited experience with tranexamic acid and no experience with aminocaproic acid and
aprotinin in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor
experience with the use of the systemic haemostatic desmopressin in individuals receiving
rivaroxaban. Due to the high plasma protein binding rivaroxaban is not expected to be dialysable.
5. PHARMACOLOGICAL PROPERTIES
Mechanism of action
Rivaroxaban is a highly selective direct factor Xa inhibitor with oral bioavailability. Inhibition of
factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting
both thrombin formation and development of thrombi. Rivaroxaban does not inhibit thrombin
(activated factor II) and no effects on platelets have been demonstrated.
Pharmacodynamic effects
Dose-dependent inhibition of factor Xa activity was observed in humans. Prothrombin time (PT) is
influenced by rivaroxaban in a dose dependent way with a close correlation to plasma concentrations
(r value equals 0.98) if Neoplastin is used for the assay. Other reagents would provide different results.
The readout for PT is to be done in seconds, because the INR (International Normalised Ratio) is only
calibrated and validated for coumarins and cannot be used for any other anticoagulant.
In patients receiving rivaroxaban for treatment of DVT and PE and prevention of recurrence, the 5/95
percentiles for PT (Neoplastin) 2 - 4 hours after tablet intake (i.e. at the time of maximum effect) for
15 mg rivaroxaban twice daily ranged from 17 to 32 s and for 20 mg rivaroxaban once daily from 15
to 30 s. At trough (8 - 16 h after tablet intake) the 5/95 percentiles for 15 mg twice daily ranged from
14 to 24 s and for 20 mg once daily (18 - 30 h after tablet intake) from 13 to 20 s.
71
In patients with non-valvular atrial fibrillation receiving rivaroxaban for the prevention of stroke and
systemic embolism, the 5/95 percentiles for PT (Neoplastin) 1 - 4 hours after tablet intake (i.e. at the
time of maximum effect) in patients treated with 20 mg once daily ranged from 14 to 40 s and in
patients with moderate renal impairment treated with 15 mg once daily from 10 to 50 s. At trough
(16 - 36 h after tablet intake) the 5/95 percentiles in patients treated with 20 mg once daily ranged
from 12 to 26 s and in patients with moderate renal impairment treated with 15 mg once daily from 12
to 26 s.
In a clinical pharmacology study on the reversal of rivaroxaban pharmacodynamics in healthy adult
subjects (n=22), the effects of single doses (50 IU/kg) of two different types of PCCs, a 3-factor PCC
(Factors II, IX and X) and a 4-factor PCC (Factors II, VII, IX and X) were assessed. The 3-factor PCC
reduced mean Neoplastin PT values by approximately 1.0 second within 30 minutes, compared to
reductions of approximately 3.5 seconds observed with the 4-factor PCC. In contrast, the 3-factor PCC
had a greater and more rapid overall effect on reversing changes in endogenous thrombin generation
than the 4-factor PCC (see section 4.9).
The activated partial thromboplastin time (aPTT) and HepTest are also prolonged dose-dependently;
however, they are not recommended to assess the pharmacodynamic effect of rivaroxaban. There is no
need for monitoring of coagulation parameters during treatment with rivaroxaban in clinical routine.
However, if clinically indicated rivaroxaban levels can be measured by calibrated quantitative anti-
factor Xa tests (see section 5.2).
Xarelto was non-inferior to warfarin for the primary composite endpoint of stroke and non-CNS
systemic embolism. In the per-protocol population on treatment, stroke or systemic embolism occurred
in 188 patients on rivaroxaban (1.71% per year) and 241 on warfarin (2.16% per year) (HR 0.79;
95% CI, 0.66 0.96; P<0.001 for non-inferiority). Among all randomised patients analysed according
to ITT, primary events occurred in 269 on rivaroxaban (2.12% per year) and 306 on warfarin (2.42%
per year) (HR 0.88; 95% CI, 0.74 1.03; P<0.001 for non-inferiority; P=0.117 for superiority).
Results for secondary endpoints as tested in hierarchical order in the ITT analysis are displayed in
Table 3.
Among patients in the warfarin group, INR values were within the therapeutic range (2.0 to 3.0) a
mean of 55% of the time (median, 58%; interquartile range, 43 to 71). The effect of rivaroxaban did
not differ across the level of centre TTR (Time in Target INR Range of 2.0 - 3.0) in the equally sized
quartiles (P=0.74 for interaction). Within the highest quartile according to centre, the hazard ratio with
rivaroxaban versus warfarin was 0.74 (95% CI, 0.49 - 1.12).
The incidence rates for the principal safety outcome (major and non-major clinically relevant bleeding
events) were similar for both treatment groups (see Table 4).
72
Table 3: Efficacy results from phase III ROCKET AF
Study population ITT analyses of efficacy in patients with non-valvular atrial fibrillation
Xarelto Warfarin
20 mg od titrated to a target INR
(15 mg od in patients of 2.5 (therapeutic Hazard ratio (95%
with moderate renal range 2.0 to 3.0) CI)
Treatment dosage
impairment) p-value, test for
superiority
Event rate (100 pt-yr) Event rate (100 pt-yr)
Non-CNS 20 27 0.74
systemic (0.16) (0.21) (0.42 - 1.32)
embolism 0.308
73
Table 4: Safety results from phase III ROCKET AF
Study population Patients with non-valvular atrial fibrillationa)
Xarelto Warfarin
20 mg once a day titrated to a target INR of
(15 mg once a day in 2.5 (therapeutic range Hazard ratio
Treatment dosage patients with moderate 2.0 to 3.0) (95% CI)
renal impairment) p-value
In addition to the phase III ROCKET AF study, a prospective, single-arm, post-authorization, non-
interventional, open-label cohort study (XANTUS) with central outcome adjudication including
thromboembolic events and major bleeding has been conducted. 6,785 patients with non-valvular
atrial fibrillation were enrolled for prevention of stroke and non-central nervous system (CNS)
systemic embolism in clinical practice. The mean CHADS2 and HAS-BLED scores were both 2.0 in
XANTUS, compared to a mean CHADS2 and HAS-BLED score of 3.5 and 2.8 in ROCKET AF,
respectively. Major bleeding occurred in 2.1 per 100 patient years. Fatal haemorrhage was reported in
0.2 per 100 patient years and intracranial haemorrhage in 0.4 per 100 patient years. Stroke or non-CNS
systemic embolism was recorded in 0.8 per 100 patient years.
These observations in clinical practice are consistent with the established safety profile in this
indication.
74
non-valvular atrial fibrillation scheduled for cardioversion to compare rivaroxaban with dose-adjusted
VKA (randomized 2:1), for the prevention of cardiovascular events. TEE- guided (1 - 5 days of pre-
treatment) or conventional cardioversion (at least three weeks of pre-treatment) strategies were
employed. The primary efficacy outcome (all stroke, transient ischemic attack, non-CNS systemic
embolism, MI and cardiovascular death) occurred in 5 (0.5 %) patients in the rivaroxaban group
(n = 978) and 5 (1.0 %) patients in the VKA group (n = 492; RR 0.50; 95 % CI 0.15-1.73; modified
ITT population). The principal safety outcome (major bleeding) occurred in 6 (0.6 %) and 4 (0.8 %)
patients in the rivaroxaban (n = 988) and VKA (n = 499) groups, respectively (RR 0.76; 95 % CI 0.21-
2.67; safety population). This exploratory study showed comparable efficacy and safety between
rivaroxaban and VKA treatment groups in the setting of cardioversion.
In Einstein DVT 3,449 patients with acute DVT were studied for the treatment of DVT and the
prevention of recurrent DVT and PE (patients who presented with symptomatic PE were excluded
from this study). The treatment duration was for 3, 6 or 12 months depending on the clinical
judgement of the investigator.
For the initial 3 week treatment of acute DVT 15 mg rivaroxaban was administered twice daily. This
was followed by 20 mg rivaroxaban once daily.
In Einstein PE, 4,832 patients with acute PE were studied for the treatment of PE and the prevention of
recurrent DVT and PE. The treatment duration was for 3, 6 or 12 months depending on the clinical
judgement of the investigator.
For the initial treatment of acute PE 15 mg rivaroxaban was administered twice daily for three weeks.
This was followed by 20 mg rivaroxaban once daily.
In both the Einstein DVT and the Einstein PE study, the comparator treatment regimen consisted of
enoxaparin administered for at least 5 days in combination with vitamin K antagonist treatment until
the PT/INR was in therapeutic range ( 2.0). Treatment was continued with a vitamin K antagonist
dose-adjusted to maintain the PT/INR values within the therapeutic range of 2.0 to 3.0.
In Einstein Extension 1,197 patients with DVT or PE were studied for the prevention of recurrent
DVT and PE. The treatment duration was for an additional 6 or 12 months in patients who had
completed 6 to 12 months of treatment for venous thromboembolism depending on the clinical
judgment of the investigator. Xarelto 20 mg once daily was compared with placebo.
All phase III studies used the same pre-defined primary and secondary efficacy outcomes. The
primary efficacy outcome was symptomatic recurrent VTE defined as the composite of recurrent DVT
or fatal or non-fatal PE. The secondary efficacy outcome was defined as the composite of recurrent
DVT, non-fatal PE and all cause mortality.
In the Einstein DVT study (see Table 5) rivaroxaban was demonstrated to be non-inferior to
enoxaparin/VKA for the primary efficacy outcome (p < 0.0001 (test for non-inferiority); hazard ratio:
0.680 (0.443 - 1.042), p=0.076 (test for superiority)). The prespecified net clinical benefit (primary
efficacy outcome plus major bleeding events) was reported with a hazard ratio of 0.67
((95% CI: 0.47 0.95), nominal p value p=0.027) in favour of rivaroxaban. INR values were within
the therapeutic range a mean of 60.3% of the time for the mean treatment duration of 189 days, and
55.4%, 60.1%, and 62.8% of the time in the 3-, 6-, and 12-month intended treatment duration groups,
respectively. In the enoxaparin/VKA group, there was no clear relation between the level of mean
centre TTR (Time in Target INR Range of 2.0 3.0) in the equally sized tertiles and the incidence of
75
the recurrent VTE (P=0.932 for interaction). Within the highest tertile according to centre, the hazard
ratio with rivaroxaban versus warfarin was 0.69 (95% CI: 0.35 - 1.35).
The incidence rates for the primary safety outcome (major or clinically relevant non-major bleeding
events) as well as the secondary safety outcome (major bleeding events) were similar for both
treatment groups.
Table 5: Efficacy and safety results from phase III Einstein DVT
Study population 3,449 patients with symptomatic acute deep vein thrombosis
Xareltoa) Enoxaparin/VKAb)
Treatment dosage and duration 3, 6 or 12 months 3, 6 or 12 months
N=1,731 N=1,718
36 51
Symptomatic recurrent VTE* (2.1%) (3.0%)
20 18
Symptomatic recurrent PE
(1.2%) (1.0%)
14 28
Symptomatic recurrent DVT
(0.8%) (1.6%)
1
Symptomatic PE and DVT 0
(0.1%)
Fatal PE/Death where PE 4 6
cannot be ruled out (0.2%) (0.3%)
Major or clinically relevant non- 139 138
major bleeding (8.1%) (8.1%)
14 20
Major bleeding events
(0.8%) (1.2%)
a) Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily
b) Enoxaparin for at least 5 days, overlapped with and followed by VKA
* p < 0.0001 (non-inferiority to a prespecified hazard ratio of 2.0); hazard ratio: 0.680
(0.443 - 1.042), p=0.076 (superiority)
The incidence rates for the primary safety outcome (major or clinically relevant non-major bleeding
events) were slightly lower in the rivaroxaban treatment group (10.3% (249/2412)) than in the
enoxaparin/VKA treatment group (11.4% (274/2405)). The incidence of the secondary safety outcome
(major bleeding events) was lower in the rivaroxaban group (1.1% (26/2412)) than in the
enoxaparin/VKA group (2.2% (52/2405)) with a hazard ratio 0.493 (95% CI: 0.308 - 0.789).
76
Table 6: Efficacy and safety results from phase III Einstein PE
Study population 4,832 patients with an acute symptomatic PE
Xareltoa) Enoxaparin/VKAb)
Treatment dosage and duration 3, 6 or 12 months 3, 6 or 12 months
N=2,419 N=2,413
50 44
Symptomatic recurrent VTE* (2.1%) (1.8%)
23 20
Symptomatic recurrent PE
(1.0%) (0.8%)
18 17
Symptomatic recurrent DVT
(0.7%) (0.7%)
2
Symptomatic PE and DVT 0
(<0.1%)
Fatal PE/Death where PE 11 7
cannot be ruled out (0.5%) (0.3%)
Major or clinically relevant non- 249 274
major bleeding (10.3%) (11.4%)
26 52
Major bleeding events
(1.1%) (2.2%)
a) Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily
b) Enoxaparin for at least 5 days, overlapped with and followed by VKA
* p < 0.0026 (non-inferiority to a prespecified hazard ratio of 2.0); hazard ratio: 1.123 (0.749
1.684)
A prespecified pooled analysis of the outcome of the Einstein DVT and PE studies was conducted (see
Table 7).
Table 7: Efficacy and safety results from pooled analysis of phase III Einstein DVT and
Einstein PE
Study population 8,281 patients with an acute symptomatic DVT or PE
Xareltoa) Enoxaparin/VKAb)
Treatment dosage and duration 3, 6 or 12 months 3, 6 or 12 months
N=4,150 N=4,131
86 95
Symptomatic recurrent VTE* (2.1%) (2.3%)
43 38
Symptomatic recurrent PE
(1.0%) (0.9%)
32 45
Symptomatic recurrent DVT
(0.8%) (1.1%)
1 2
Symptomatic PE and DVT
(<0.1%) (<0.1%)
Fatal PE/Death where PE 15 13
cannot be ruled out (0.4%) (0.3%)
Major or clinically relevant non- 388 412
major bleeding (9.4%) (10.0%)
40 72
Major bleeding events
(1.0%) (1.7%)
a) Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily
b) Enoxaparin for at least 5 days, overlapped with and followed by VKA
* p < 0.0001 (non-inferiority to a prespecified hazard ratio of 1.75); hazard ratio: 0.886 (0.661
1.186)
The prespecified net clinical benefit (primary efficacy outcome plus major bleeding events) of the
pooled analysis was reported with a hazard ratio of 0.771 ((95% CI: 0.614 0.967), nominal p value
p= 0.0244).
77
In the Einstein Extension study (see Table 8) rivaroxaban was superior to placebo for the primary and
secondary efficacy outcomes. For the primary safety outcome (major bleeding events) there was a
non-significant numerically higher incidence rate for patients treated with rivaroxaban 20 mg once
daily compared to placebo. The secondary safety outcome (major or clinically relevant non-major
bleeding events) showed higher rates for patients treated with rivaroxaban 20 mg once daily compared
to placebo.
Table 8: Efficacy and safety results from phase III Einstein Extension
1,197 patients continued treatment and prevention
Study population
of recurrent venous thromboembolism
Xareltoa) Placebo
Treatment dosage and duration 6 or 12 months 6 or 12 months
N=602 N=594
8 42
Symptomatic recurrent VTE* (1.3%) (7.1%)
2 13
Symptomatic recurrent PE
(0.3%) (2.2%)
5 31
Symptomatic recurrent DVT
(0.8%) (5.2%)
Fatal PE/Death where PE 1 1
cannot be ruled out (0.2%) (0.2%)
4 0
Major bleeding events
(0.7%) (0.0%)
Clinically relevant non-major 32 7
bleeding (5.4%) (1.2%)
a) Rivaroxaban 20 mg once daily
* p < 0.0001 (superiority), hazard ratio: 0.185 (0.087 - 0.393)
In addition to the phase III EINSTEIN program, a prospective, non-interventional, open-label cohort
study (XALIA) with central outcome adjudication including recurrent VTE, major bleeding and death
has been conducted. 5,142 patients with acute DVT were enrolled to investigate the long-term safety
of rivaroxaban compared with standard-of-care anticoagulation therapy in clinical practice. Rates of
major bleeding, recurrent VTE and all-cause mortality for rivaroxaban were 0.7%, 1.4% and 0.5%,
respectively. There were differences in patient baseline characteristics including age, cancer and renal
impairment. A pre-specified propensity score stratified analysis was used to adjust for measured
baseline differences but residual confounding may, in spite of this, influence the results. Adjusted
hazard ratios comparing rivaroxaban and standard-of-care for major bleeding, recurrent VTE and all-
cause mortality were 0.77 (95% CI 0.40 - 1.50), 0.91 (95% CI 0.54 - 1.54) and 0.51 (95% CI
0.24 - 1.07), respectively.
These results in clinical practice are consistent with the established safety profile in this indication.
Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with
Xarelto in one or more subsets of the paediatric population in the treatment of thromboembolic events.
The European Medicines Agency has waived the obligation to submit the results of studies with
Xarelto in all subsets of the paediatric population in the prevention of thromboembolic events (see
section 4.2 for information on paediatric use).
Absorption
Rivaroxaban is rapidly absorbed with maximum concentrations (Cmax) appearing 2 - 4 hours after
tablet intake.
Oral absorption of rivaroxaban is almost complete and oral bioavailability is high (80 - 100%) for the
2.5 mg and 10 mg tablet dose, irrespective of fasting/fed conditions. Intake with food does not affect
rivaroxaban AUC or Cmax at the 2.5 mg and 10 mg dose.
78
Due to a reduced extent of absorption an oral bioavailability of 66% was determined for the 20 mg
tablet under fasting conditions. When Xarelto 20 mg tablets are taken together with food increases in
mean AUC by 39% were observed when compared to tablet intake under fasting conditions, indicating
almost complete absorption and high oral bioavailability. Xarelto 15 mg and 20 mg are to be taken
with food (see section 4.2).
Rivaroxaban pharmacokinetics are approximately linear up to about 15 mg once daily in fasting state.
Under fed conditions Xarelto 10 mg, 15 mg and 20 mg tablets demonstrated dose-proportionality. At
higher doses rivaroxaban displays dissolution limited absorption with decreased bioavailability and
decreased absorption rate with increased dose.
Variability in rivaroxaban pharmacokinetics is moderate with inter-individual variability (CV%)
ranging from 30% to 40%.
Absorption of rivaroxaban is dependent on the site of its release in the gastrointestinal tract. A 29%
and 56% decrease in AUC and Cmax compared to tablet was reported when rivaroxaban granulate is
released in the proximal small intestine. Exposure is further reduced when rivaroxaban is released in
the distal small intestine, or ascending colon. Therefore, administration of rivaroxaban distal to the
stomach should be avoided since this can result in reduced absorption and related rivaroxaban
exposure.
Bioavailability (AUC and Cmax) was comparable for 20 mg rivaroxaban administered orally as a
crushed tablet mixed in apple puree, or suspended in water and administered via a gastric tube
followed by a liquid meal, compared to a whole tablet. Given the predictable, dose-proportional
pharmacokinetic profile of rivaroxaban, the bioavailability results from this study are likely applicable
to lower rivaroxaban doses.
Distribution
Plasma protein binding in humans is high at approximately 92 % to 95 %, with serum albumin being
the main binding component. The volume of distribution is moderate with Vss being approximately
50 litres.
Special populations
Gender
There were no clinically relevant differences in pharmacokinetics and pharmacodynamics between
male and female patients.
Elderly population
Elderly patients exhibited higher plasma concentrations than younger patients, with mean AUC values
being approximately 1.5 fold higher, mainly due to reduced (apparent) total and renal clearance. No
dose adjustment is necessary.
79
Inter-ethnic differences
No clinically relevant inter-ethnic differences among Caucasian, African-American, Hispanic,
Japanese or Chinese patients were observed regarding rivaroxaban pharmacokinetics and
pharmacodynamics.
Hepatic impairment
Cirrhotic patients with mild hepatic impairment (classified as Child Pugh A) exhibited only minor
changes in rivaroxaban pharmacokinetics (1.2 fold increase in rivaroxaban AUC on average), nearly
comparable to their matched healthy control group. In cirrhotic patients with moderate hepatic
impairment (classified as Child Pugh B), rivaroxaban mean AUC was significantly increased by
2.3 fold compared to healthy volunteers. Unbound AUC was increased 2.6 fold. These patients also
had reduced renal elimination of rivaroxaban, similar to patients with moderate renal impairment.
There are no data in patients with severe hepatic impairment.
The inhibition of factor Xa activity was increased by a factor of 2.6 in patients with moderate hepatic
impairment as compared to healthy volunteers; prolongation of PT was similarly increased by a factor
of 2.1. Patients with moderate hepatic impairment were more sensitive to rivaroxaban resulting in a
steeper PK/PD relationship between concentration and PT.
Xarelto is contraindicated in patients with hepatic disease associated with coagulopathy and clinically
relevant bleeding risk, including cirrhotic patients with Child Pugh B and C (see section 4.3).
Renal impairment
There was an increase in rivaroxaban exposure correlated to decrease in renal function, as assessed via
creatinine clearance measurements. In individuals with mild (creatinine clearance 50 - 80 ml/min),
moderate (creatinine clearance 30 - 49 ml/min) and severe (creatinine clearance 15 - 29 ml/min) renal
impairment, rivaroxaban plasma concentrations (AUC) were increased 1.4, 1.5 and 1.6 fold
respectively. Corresponding increases in pharmacodynamic effects were more pronounced. In
individuals with mild, moderate and severe renal impairment the overall inhibition of factor Xa
activity was increased by a factor of 1.5, 1.9 and 2.0 respectively as compared to healthy volunteers;
prolongation of PT was similarly increased by a factor of 1.3, 2.2 and 2.4 respectively. There are no
data in patients with creatinine clearance < 15 ml/min.
Due to the high plasma protein binding rivaroxaban is not expected to be dialysable.
Use is not recommended in patients with creatinine clearance < 15 ml/min. Xarelto is to be used with
caution in patients with creatinine clearance 15 - 29 ml/min (see section 4.4).
Pharmacokinetic/pharmacodynamic relationship
The pharmacokinetic/pharmacodynamic (PK/PD) relationship between rivaroxaban plasma
concentration and several PD endpoints (factor Xa inhibition, PT, aPTT, Heptest) has been evaluated
after administration of a wide range of doses (5 - 30 mg twice a day). The relationship between
rivaroxaban concentration and factor Xa activity was best described by an Emax model. For PT, the
linear intercept model generally described the data better. Depending on the different PT reagents
used, the slope differed considerably. When Neoplastin PT was used, baseline PT was about 13 s and
the slope was around 3 to 4 s/(100 g/l). The results of the PK/PD analyses in Phase II and III were
consistent with the data established in healthy subjects.
Paediatric population
Safety and efficacy have not been established for children and adolescents up to 18 years.
80
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, single dose toxicity, phototoxicity, genotoxicity, carcinogenic potential and juvenile
toxicity.
Effects observed in repeat-dose toxicity studies were mainly due to the exaggerated pharmacodynamic
activity of rivaroxaban. In rats, increased IgG and IgA plasma levels were seen at clinically relevant
exposure levels.
In rats, no effects on male or female fertility were seen. Animal studies have shown reproductive
toxicity related to the pharmacological mode of action of rivaroxaban (e.g. haemorrhagic
complications). Embryo-foetal toxicity (post-implantation loss, retarded/progressed ossification,
hepatic multiple light coloured spots) and an increased incidence of common malformations as well as
placental changes were observed at clinically relevant plasma concentrations. In the pre- and post-
natal study in rats, reduced viability of the offspring was observed at doses that were toxic to the dams.
6. PHARMACEUTICAL PARTICULARS
Tablet core:
Microcrystalline cellulose
Croscarmellose sodium
Lactose monohydrate
Hypromellose
Sodium laurilsulfate
Magnesium stearate
Film-coat:
Macrogol 3350
Hypromellose
Titanium dioxide (E 171)
Iron oxide red (E 172)
6.2 Incompatibilities
Not applicable.
3 years
This medicinal product does not require any special storage conditions.
PP/Aluminium foil blisters in cartons of 10, 14, 28 or 98 film-coated tablets or perforated unit dose
blisters in cartons of 10 x 1, or 100 x 1 or in multipacks containing 100 (10 packs of 10 x 1) film-
coated tablets.
HDPE bottles of 100 film-coated tablets with a PP screw cap.
PP/Aluminium foil blisters in a wallet containing 42 film-coated tablets Xarelto 15 mg and 7 film-
coated tablets Xarelto 20 mg (treatment initiation pack).
81
6.6 Special precautions for disposal
Bayer Pharma AG
13342 Berlin
Germany
{MM/YYYY}
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu.
82
Treatment Initiation Pack
This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
See section 4.8 for how to report adverse reactions.
3. PHARMACEUTICAL FORM
4. CLINICAL PARTICULARS
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent
DVT and PE in adults. (See section 4.4 for haemodynamically unstable PE patients.)
Posology
Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE
The recommended dose for the initial treatment of acute DVT or PE is 15 mg twice daily for the first
three weeks followed by 20 mg once daily for the continued treatment and prevention of recurrent
DVT and PE, as indicated in the table below.
The 4-week treatment initiation pack of Xarelto is dedicated to patients who will transition from
15 mg twice daily to 20 mg once daily from Day 22 onwards (see section 6.5).
83
For patients with moderate or severe renal impairment where the decision has been taken for 15 mg
once daily from Day 22 onwards, other presentations only containing 15 mg film-coated tablets are
available (see dosing instructions in section Special populations below).
The duration of therapy should be individualised after careful assessment of the treatment benefit
against the risk for bleeding (see section 4.4). Short duration of therapy (at least 3 months) should be
based on transient risk factors (e.g. recent surgery, trauma, immobilisation) and longer durations
should be based on permanent risk factors or idiopathic DVT or PE.
If a dose is missed during the 15 mg twice daily treatment phase (day 1 - 21), the patient should take
Xarelto immediately to ensure intake of 30 mg Xarelto per day. In this case two 15 mg tablets may be
taken at once. The patient should continue with the regular 15 mg twice daily intake as recommended
on the following day.
If a dose is missed during the once daily treatment phase (day 22 and onwards), the patient should take
Xarelto immediately, and continue on the following day with the once daily intake as recommended.
The dose should not be doubled within the same day to make up for a missed dose.
Special populations
Renal impairment
Limited clinical data for patients with severe renal impairment (creatinine clearance 15 - 29 ml/min)
indicate that rivaroxaban plasma concentrations are significantly increased. Therefore, Xarelto is to be
used with caution in these patients. Use is not recommended in patients with creatinine clearance
< 15 ml/min (see sections 4.4 and 5.2).
- For the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE: Patients
should be treated with 15 mg twice daily for the first 3 weeks.
84
Thereafter, the recommended dose is 20 mg once daily. A reduction of the dose from 20 mg
once daily to 15 mg once daily should be considered if the patients assessed risk for bleeding
outweighs the risk for recurrent DVT and PE. The recommendation for the use of 15 mg is
based on PK modelling and has not been studied in this clinical setting (see sections 4.4, 5.1 and
5.2).
No dose adjustment is necessary in patients with mild renal impairment (creatinine clearance
50 - 80 ml/min) (see section 5.2).
Hepatic impairment
Xarelto is contraindicated in patients with hepatic disease associated with coagulopathy and clinically
relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see sections 4.3 and 5.2).
Elderly population
No dose adjustment (see section 5.2).
Body weight
No dose adjustment (see section 5.2).
Gender
No dose adjustment (see section 5.2).
Paediatric population
The safety and efficacy of Xarelto in children aged 0 to 18 years have not been established. No data
are available. Therefore, Xarelto is not recommended for use in children below 18 years of age.
Method of administration
For oral use.
The tablets are to be taken with food (see section 5.2).
For patients who are unable to swallow whole tablets, Xarelto tablet may be crushed and mixed with
water or apple puree immediately prior to use and administered orally. After the administration of
crushed Xarelto 15 mg or 20 mg film-coated tablets, the dose should be immediately followed by
food.
The crushed Xarelto tablet may also be given through gastric tubes after confirmation of the correct
gastric placement of the tube. The crushed tablet should be administered in a small amount of water
via a gastric tube after which it should be flushed with water. After the administration of crushed
Xarelto15 mg or 20 mg film-coated tablets, the dose should then be immediately followed by enteral
feeding (see section 5.2).
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Lesion or condition, if considered to be a significant risk for major bleeding. This may include current
or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent
brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage,
known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major
intraspinal or intracerebral vascular abnormalities.
Concomitant treatment with any other anticoagulants e.g. unfractionated heparin (UFH), low
molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral
anticoagulants (warfarin, dabigatran etexilate, apixaban, etc.) except under specific circumstances of
switching anticoagulant therapy (see section 4.2) or when UFH is given at doses necessary to maintain
an open central venous or arterial catheter (see section 4.5).
85
Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic
patients with Child Pugh B and C (see section 5.2).
Clinical surveillance in line with anticoagulation practice is recommended throughout the treatment
period.
Haemorrhagic risk
As with other anticoagulants, patients taking Xarelto are to be carefully observed for signs of bleeding.
It is recommended to be used with caution in conditions with increased risk of haemorrhage. Xarelto
administration should be discontinued if severe haemorrhage occurs.
In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary) and
anaemia were seen more frequently during long term rivaroxaban treatment compared with VKA
treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of
haemoglobin/haematocrit could be of value to detect occult bleeding, as judged to be appropriate.
Several sub-groups of patients, as detailed below, are at increased risk of bleeding. These patients are
to be carefully monitored for signs and symptoms of bleeding complications and anaemia after
initiation of treatment (see section 4.8).
Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site.
Although treatment with rivaroxaban does not require routine monitoring of exposure, rivaroxaban
levels measured with a calibrated quantitative anti-factor Xa assay may be useful in exceptional
situations where knowledge of rivaroxaban exposure may help to inform clinical decisions, e.g.,
overdose and emergency surgery (see sections 5.1 and 5.2).
Renal impairment
In patients with severe renal impairment (creatinine clearance < 30 ml/min) rivaroxaban plasma levels
may be significantly increased (1.6 fold on average) which may lead to an increased bleeding risk.
Xarelto is to be used with caution in patients with creatinine clearance 15 - 29 ml/min. Use is not
recommended in patients with creatinine clearance < 15 ml/min (see sections 4.2 and 5.2).
Xarelto should be used with caution in patients with renal impairment concomitantly receiving other
medicinal products which increase rivaroxaban plasma concentrations (see section 4.5).
Care is to be taken if patients are treated concomitantly with medicinal products affecting haemostasis
such as non-steroidal anti-inflammatory medicinal products (NSAIDs), acetylsalicylic acid and
platelet aggregation inhibitors. For patients at risk of ulcerative gastrointestinal disease an appropriate
prophylactic treatment may be considered (see section 4.5).
86
Other haemorrhagic risk factors
As with other antithrombotics, rivaroxaban is not recommended in patients with an increased bleeding
risk such as:
congenital or acquired bleeding disorders
uncontrolled severe arterial hypertension
other gastrointestinal disease without active ulceration that can potentially lead to bleeding
complications (e.g. inflammatory bowel disease, oesophagitis, gastritis and gastroesophageal
reflux disease)
vascular retinopathy
bronchiectasis or history of pulmonary bleeding
Dosing recommendations before and after invasive procedures and surgical intervention
If an invasive procedure or surgical intervention is required, Xarelto 15 mg/ Xarelto 20 mg should be
stopped at least 24 hours before the intervention, if possible and based on the clinical judgement of the
physician.
If the procedure cannot be delayed the increased risk of bleeding should be assessed against the
urgency of the intervention.
Xarelto should be restarted as soon as possible after the invasive procedure or surgical intervention
provided the clinical situation allows and adequate haemostasis has been established as determined by
the treating physician (see section 5.2).
Elderly population
Increasing age may increase haemorrhagic risk (see section 5.2).
87
4.5 Interaction with other medicinal products and other forms of interaction
Active substances strongly inhibiting only one of the rivaroxaban elimination pathways, either
CYP3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent.
Clarithromycin (500 mg twice a day), for instance, considered as a strong CYP3A4 inhibitor and
moderate P-gp inhibitor, led to a 1.5 fold increase in mean rivaroxaban AUC and a 1.4 fold increase in
Cmax. This increase is not considered clinically relevant. (For patients with renal impairment: see
section 4.4).
Erythromycin (500 mg three times a day), which inhibits CYP3A4 and P-gp moderately, led to a
1.3 fold increase in mean rivaroxaban AUC and Cmax. This increase is not considered clinically
relevant.
In subjects with mild renal impairment erythromycin (500 mg three times a day) led to a 1.8 fold
increase in mean rivaroxaban AUC and 1.6 fold increase in C max when compared to subjects with
R
normal renal function. In subjects with moderate renal impairment, erythromycin led to a 2.0 fold
increase in mean rivaroxaban AUC and 1.6 fold increase in C max when compared to subjects with
R
normal renal function. The effect of erythromycin is additive to that of renal impairment (see section
4.4).
Fluconazole (400 mg once daily), considered as a moderate CYP3A4 inhibitor, led to a 1.4 fold
increase in mean rivaroxaban AUC and a 1.3 fold increase in mean Cmax. This increase is not
considered clinically relevant. (For patients with renal impairment: see section 4.4).
Given the limited clinical data available with dronedarone, co-administration with rivaroxaban should
be avoided.
Anticoagulants
After combined administration of enoxaparin (40 mg single dose) with rivaroxaban (10 mg single
dose) an additive effect on anti-factor Xa activity was observed without any additional effects on
clotting tests (PT, aPTT). Enoxaparin did not affect the pharmacokinetics of rivaroxaban.
Due to the increased bleeding risk care is to be taken if patients are treated concomitantly with any
other anticoagulants (see sections 4.3 and 4.4).
88
Warfarin
Converting patients from the vitamin K antagonist warfarin (INR 2.0 to 3.0) to rivaroxaban (20 mg) or
from rivaroxaban (20 mg) to warfarin (INR 2.0 to 3.0) increased prothrombin time/INR (Neoplastin)
more than additively (individual INR values up to 12 may be observed), whereas effects on aPTT,
inhibition of factor Xa activity and endogenous thrombin potential were additive.
If it is desired to test the pharmacodynamic effects of rivaroxaban during the conversion period, anti-
factor Xa activity, PiCT, and Heptest can be used as these tests were not affected by warfarin. On the
fourth day after the last dose of warfarin, all tests (including PT, aPTT, inhibition of factor Xa activity
and ETP) reflected only the effect of rivaroxaban.
If it is desired to test the pharmacodynamic effects of warfarin during the conversion period, INR
measurement can be used at the Ctrough of rivaroxaban (24 hours after the previous intake of
rivaroxaban) as this test is minimally affected by rivaroxaban at this time point.
No pharmacokinetic interaction was observed between warfarin and rivaroxaban.
CYP3A4 inducers
Co-administration of rivaroxaban with the strong CYP3A4 inducer rifampicin led to an approximate
50 % decrease in mean rivaroxaban AUC, with parallel decreases in its pharmacodynamic effects. The
concomitant use of rivaroxaban with other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine,
phenobarbital or St. Johns Wort (Hypericum perforatum)) may also lead to reduced rivaroxaban
plasma concentrations. Therefore, concomitant administration of strong CYP3A4 inducers should be
avoided unless the patient is closely observed for signs and symptoms of thrombosis.
Laboratory parameters
Clotting parameters (e.g. PT, aPTT, HepTest) are affected as expected by the mode of action of
rivaroxaban (see section 5.1).
Pregnancy
Safety and efficacy of Xarelto have not been established in pregnant women. Studies in animals have
shown reproductive toxicity (see section 5.3). Due to the potential reproductive toxicity, the intrinsic
risk of bleeding and the evidence that rivaroxaban passes the placenta, Xarelto is contraindicated
during pregnancy (see section 4.3).
Women of child-bearing potential should avoid becoming pregnant during treatment with rivaroxaban.
Breast feeding
Safety and efficacy of Xarelto have not been established in breast feeding women. Data from animals
indicate that rivaroxaban is secreted into milk. Therefore Xarelto is contraindicated during breast
feeding (see section 4.3). A decision must be made whether to discontinue breast feeding or to
discontinue/abstain from therapy.
Fertility
No specific studies with rivaroxaban in humans have been conducted to evaluate effects on fertility. In
a study on male and female fertility in rats no effects were seen (see section 5.3).
Xarelto has minor influence on the ability to drive and use machines. Adverse reactions like syncope
(frequency: uncommon) and dizziness (frequency: common) have been reported (see section 4.8).
Patients experiencing these adverse reactions should not drive or use machines.
89
4.8 Undesirable effects
Table 1: Number of patients studied, maximum daily dose and treatment duration in phase III
studies
Indication Number Maximum daily Maximum
of dose treatment duration
patients*
Prevention of venous thromboembolism 6,097 10 mg 39 days
(VTE) in adult patients undergoing
elective hip or knee replacement surgery
Prevention of venous thromboembolism 3,997 10 mg 39 days
in medically ill patients
Treatment of DVT, PE and prevention 4,556 Day 1 - 21: 30 mg 21 months
of recurrence Day 22 and onwards:
20 mg
Prevention of stroke and systemic 7,750 20 mg 41 months
embolism in patients with non-valvular
atrial fibrillation
Prevention of atherothrombotic events in 10,225 5 mg or 10 mg 31 months
patients after an ACS respectively, co-
administered with
either ASA or ASA
plus clopidogrel or
ticlopidine
*Patients exposed to at least one dose of rivaroxaban
The most commonly reported adverse reactions in patients receiving rivaroxaban were bleedings (see
section 4.4. and Description of selected adverse reactions below). The most commonly reported
bleedings (4 %) were epistaxis (5.9 %) and gastrointestinal tract haemorrhage (4.2 %).
In total about 67% of patients exposed to at least one dose of rivaroxaban were reported with treatment
emergent adverse events. About 22% of the patients experienced adverse events considered related to
treatment as assessed by investigators. In patients treated with 10 mg Xarelto undergoing hip or knee
replacement surgery and in hospitalised medically ill patients, bleeding events occurred in
approximately 6.8% and 12.6% of patients, respectively, and anaemia occurred in approximately 5.9%
and 2.1% of patients, respectively. In patients treated with either 15 mg twice daily Xarelto followed
by 20 mg once daily for treatment of DVT or PE, or with 20 mg once daily for prevention of recurrent
DVT and PE, bleeding events occurred in approximately 27.8% of patients and anaemia occurred in
approximately 2.2% of patients. In patients treated for prevention of stroke and systemic embolism,
bleeding of any type or severity was reported with an event rate of 28 per 100 patient years, and
anaemia with an event rate of 2.5 per 100 patient years. In patients treated for prevention of
cardiovascular death and myocardial infarction after an acute coronary syndrome (ACS), bleeding of
any type or severity was reported with an event rate of 22 per 100 patient years. Anaemia was reported
with an event rate of 1.4 per 100 patient years.
90
very rare ( < 1/10,000)
not known (cannot be estimated from the available data)
Table 2: All treatment-emergent adverse reactions reported in patients in phase III studies
Common Uncommon Rare Not known
91
Common Uncommon Rare Not known
92
Description of selected adverse reactions
Due to the pharmacological mode of action, the use of Xarelto may be associated with an increased
risk of occult or overt bleeding from any tissue or organ which may result in post haemorrhagic
anaemia. The signs, symptoms, and severity (including fatal outcome) will vary according to the
location and degree or extent of the bleeding and/or anaemia (see section 4.9 Management of
bleeding). In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito
urinary) and anaemia were seen more frequently during long term rivaroxaban treatment compared
with VKA treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of
haemoglobin/haematocrit could be of value to detect occult bleeding, as judged to be appropriate. The
risk of bleedings may be increased in certain patient groups e.g. those patients with uncontrolled
severe arterial hypertension and/or on concomitant treatment affecting haemostasis (see Haemorrhagic
risk in section 4.4). Menstrual bleeding may be intensified and/or prolonged. Haemorrhagic
complications may present as weakness, paleness, dizziness, headache or unexplained swelling,
dyspnoea and unexplained shock. In some cases as a consequence of anaemia, symptoms of cardiac
ischaemia like chest pain or angina pectoris have been observed.
Known complications secondary to severe bleeding such as compartment syndrome and renal failure
due to hypoperfusion have been reported for Xarelto. Therefore, the possibility of haemorrhage is to
be considered in evaluating the condition in any anticoagulated patient.
Post-marketing observations
The following adverse reactions have been reported post-marketing in temporal association with the
use of Xarelto. The frequency of these adverse reactions reported from post-marketing experience
cannot be estimated.
Immune system disorders: Angioedema and allergic oedema (In the pooled phase III trials, these
events were uncommon ( 1/1,000 to < 1/100)).
Hepatobiliary disorders: Cholestasis, Hepatitis (incl. hepatocellular injury) (In the pooled phase III
trials, these events were rare ( 1/10,000 to < 1/1,000)).
Blood and lymphatic system disorders: Thrombocytopenia (In the pooled phase III trials, these events
were uncommon ( 1/1,000 to < 1/100)).
4.9 Overdose
Rare cases of overdose up to 600 mg have been reported without bleeding complications or other
adverse reactions. Due to limited absorption a ceiling effect with no further increase in average plasma
exposure is expected at supratherapeutic doses of 50 mg rivaroxaban or above.
A specific antidote antagonising the pharmacodynamic effect of rivaroxaban is not available.
The use of activated charcoal to reduce absorption in case of rivaroxaban overdose may be considered.
Management of bleeding
Should a bleeding complication arise in a patient receiving rivaroxaban, the next rivaroxaban
administration should be delayed or treatment should be discontinued as appropriate. Rivaroxaban has
a half-life of approximately 5 to 13 hours (see section 5.2). Management should be individualised
according to the severity and location of the haemorrhage. Appropriate symptomatic treatment could
be used as needed, such as mechanical compression (e.g. for severe epistaxis), surgical haemostasis
with bleeding control procedures, fluid replacement and haemodynamic support, blood products
(packed red cells or fresh frozen plasma, depending on associated anaemia or coagulopathy) or
platelets.
If bleeding cannot be controlled by the above measures, administration of a specific procoagulant
reversal agent should be considered, such as prothrombin complex concentrate (PCC), activated
prothrombin complex concentrate (APCC) or recombinant factor VIIa (r-FVIIa). However, there is
currently very limited clinical experience with the use of these products in individuals receiving
93
rivaroxaban. The recommendation is also based on limited non-clinical data. Re-dosing of
recombinant factor VIIa shall be considered and titrated depending on improvement of bleeding.
Depending on local availability, a consultation with a coagulation expert should be considered in case
of major bleedings (see section 5.1).
Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban.
There is limited experience with tranexamic acid and no experience with aminocaproic acid and
aprotinin in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor
experience with the use of the systemic haemostatic desmopressin in individuals receiving
rivaroxaban. Due to the high plasma protein binding rivaroxaban is not expected to be dialysable.
5. PHARMACOLOGICAL PROPERTIES
Mechanism of action
Rivaroxaban is a highly selective direct factor Xa inhibitor with oral bioavailability. Inhibition of
factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting
both thrombin formation and development of thrombi. Rivaroxaban does not inhibit thrombin
(activated Factor II) and no effects on platelets have been demonstrated.
Pharmacodynamic effects
Dose-dependent inhibition of factor Xa activity was observed in humans. Prothrombin time (PT) is
influenced by rivaroxaban in a dose dependent way with a close correlation to plasma concentrations
(r value equals 0.98) if Neoplastin is used for the assay. Other reagents would provide different results.
The readout for PT is to be done in seconds, because the INR (International Normalised Ratio) is only
calibrated and validated for coumarins and cannot be used for any other anticoagulant.
In patients receiving rivaroxaban for treatment of DVT and PE and prevention of recurrence, the 5/95
percentiles for PT (Neoplastin) 2 - 4 hours after tablet intake (i.e. at the time of maximum effect) for
15 mg rivaroxaban twice daily ranged from 17 to 32 s and for 20 mg rivaroxaban once daily from 15
to 30 s. At trough (8 - 16 h after tablet intake) the 5/95 percentiles for 15 mg twice daily ranged from
14 to 24 s and for 20 mg once daily (18 - 30 h after tablet intake) from 13 to 20 s.
In patients with non-valvular atrial fibrillation receiving rivaroxaban for the prevention of stroke and
systemic embolism, the 5/95 percentiles for PT (Neoplastin) 1 - 4 hours after tablet intake (i.e. at the
time of maximum effect) in patients treated with 20 mg once daily ranged from 14 to 40 s and in
patients with moderate renal impairment treated with 15 mg once daily from 10 to 50 s. At trough
(16 - 36 h after tablet intake) the 5/95 percentiles in patients treated with 20 mg once daily ranged
from 12 to 26 s and in patients with moderate renal impairment treated with 15 mg once daily from 12
to 26 s.
In a clinical pharmacology study on the reversal of rivaroxaban pharmacodynamics in healthy adult
subjects (n=22), the effects of single doses (50 IU/kg) of two different types of PCCs, a 3-factor PCC
(Factors II, IX and X) and a 4-factor PCC (Factors II, VII, IX and X) were assessed. The 3-factor PCC
reduced mean Neoplastin PT values by approximately 1.0 second within 30 minutes, compared to
reductions of approximately 3.5 seconds observed with the 4-factor PCC. In contrast, the 3-factor PCC
had a greater and more rapid overall effect on reversing changes in endogenous thrombin generation
than the 4-factor PCC (see section 4.9).
The activated partial thromboplastin time (aPTT) and HepTest are also prolonged dose-dependently;
however, they are not recommended to assess the pharmacodynamic effect of rivaroxaban. There is no
need for monitoring of coagulation parameters during treatment with rivaroxaban in clinical routine.
However, if clinically indicated rivaroxaban levels can be measured by calibrated quantitative anti-
factor Xa tests (see section 5.2).
94
Clinical efficacy and safety
Treatment of DVT, PE and prevention of recurrent DVT and PE
The Xarelto clinical program was designed to demonstrate the efficacy of Xarelto in the initial and
continued treatment of acute DVT and PE and prevention of recurrence.
Over 9,400 patients were studied in three randomised controlled phase III clinical studies (Einstein
DVT, Einstein PE and Einstein Extension) and additionally a predefined pooled analysis of the
Einstein DVT and Einstein PE studies was conducted. The overall combined treatment duration in all
studies was up to 21 months.
In Einstein DVT 3,449 patients with acute DVT were studied for the treatment of DVT and the
prevention of recurrent DVT and PE (patients who presented with symptomatic PE were excluded
from this study). The treatment duration was for 3, 6 or 12 months depending on the clinical
judgement of the investigator.
For the initial 3 week treatment of acute DVT 15 mg rivaroxaban was administered twice daily. This
was followed by 20 mg rivaroxaban once daily.
In Einstein PE, 4,832 patients with acute PE were studied for the treatment of PE and the prevention of
recurrent DVT and PE. The treatment duration was for 3, 6 or 12 months depending on the clinical
judgement of the investigator.
For the initial treatment of acute PE 15 mg rivaroxaban was administered twice daily for three weeks.
This was followed by 20 mg rivaroxaban once daily.
In both the Einstein DVT and the Einstein PE study, the comparator treatment regimen consisted of
enoxaparin administered for at least 5 days in combination with vitamin K antagonist treatment until
the PT/INR was in therapeutic range ( 2.0). Treatment was continued with a vitamin K antagonist
dose-adjusted to maintain the PT/INR values within the therapeutic range of 2.0 to 3.0.
In Einstein Extension 1,197 patients with DVT or PE were studied for the prevention of recurrent
DVT and PE. The treatment duration was for an additional 6 or 12 months in patients who had
completed 6 to 12 months of treatment for venous thromboembolism depending on the clinical
judgment of the investigator. Xarelto 20 mg once daily was compared with placebo.
All phase III studies used the same pre-defined primary and secondary efficacy outcomes. The
primary efficacy outcome was symptomatic recurrent VTE defined as the composite of recurrent DVT
or fatal or non-fatal PE. The secondary efficacy outcome was defined as the composite of recurrent
DVT, non-fatal PE and all cause mortality.
In the Einstein DVT study (see Table 3) rivaroxaban was demonstrated to be non-inferior to
enoxaparin/VKA for the primary efficacy outcome (p < 0.0001 (test for non-inferiority); hazard ratio:
0.680 (0.443 - 1.042), p=0.076 (test for superiority)). The prespecified net clinical benefit (primary
efficacy outcome plus major bleeding events) was reported with a hazard ratio of 0.67
((95% CI: 0.47 - 0.95), nominal p value p=0.027) in favour of rivaroxaban. INR values were within
the therapeutic range a mean of 60.3% of the time for the mean treatment duration of 189 days, and
55.4%, 60.1%, and 62.8% of the time in the 3-, 6-, and 12-month intended treatment duration groups,
respectively. In the enoxaparin/VKA group, there was no clear relation between the level of mean
centre TTR (Time in Target INR Range of 2.0 3.0) in the equally sized tertiles and the incidence of
the recurrent VTE (P=0.932 for interaction). Within the highest tertile according to centre, the hazard
ratio with rivaroxaban versus warfarin was 0.69 (95% CI: 0.35 - 1.35).
The incidence rates for the primary safety outcome (major or clinically relevant non-major bleeding
events) as well as the secondary safety outcome (major bleeding events) were similar for both
treatment groups.
95
Table 3: Efficacy and safety results from phase III Einstein DVT
Study population 3,449 patients with symptomatic acute deep vein thrombosis
Xareltoa) Enoxaparin/VKAb)
Treatment dosage and duration 3, 6 or 12 months 3, 6 or 12 months
N=1,731 N=1,718
36 51
Symptomatic recurrent VTE* (2.1%) (3.0%)
20 18
Symptomatic recurrent PE
(1.2%) (1.0%)
14 28
Symptomatic recurrent DVT
(0.8%) (1.6%)
1
Symptomatic PE and DVT 0
(0.1%)
Fatal PE/Death where PE 4 6
cannot be ruled out (0.2%) (0.3%)
Major or clinically relevant non- 139 138
major bleeding (8.1%) (8.1%)
14 20
Major bleeding events
(0.8%) (1.2%)
a) Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily
b) Enoxaparin for at least 5 days, overlapped with and followed by VKA
* p < 0.0001 (non-inferiority to a prespecified hazard ratio of 2.0); hazard ratio: 0.680
(0.443 - 1.042), p=0.076 (superiority)
The incidence rates for the primary safety outcome (major or clinically relevant non-major bleeding
events) were slightly lower in the rivaroxaban treatment group (10.3% (249/2412)) than in the
enoxaparin/VKA treatment group (11.4% (274/2405)). The incidence of the secondary safety outcome
(major bleeding events) was lower in the rivaroxaban group (1.1% (26/2412)) than in the
enoxaparin/VKA group (2.2% (52/2405)) with a hazard ratio 0.493 (95% CI: 0.308 - 0.789).
96
Table 4: Efficacy and safety results from phase III Einstein PE
Study population 4,832 patients with an acute symptomatic PE
Xareltoa) Enoxaparin/VKAb)
Treatment dosage and duration 3, 6 or 12 months 3, 6 or 12 months
N=2,419 N=2,413
50 44
Symptomatic recurrent VTE* (2.1%) (1.8%)
23 20
Symptomatic recurrent PE
(1.0%) (0.8%)
18 17
Symptomatic recurrent DVT
(0.7%) (0.7%)
2
Symptomatic PE and DVT 0
(<0.1%)
Fatal PE/Death where PE 11 7
cannot be ruled out (0.5%) (0.3%)
Major or clinically relevant non- 249 274
major bleeding (10.3%) (11.4%)
26 52
Major bleeding events
(1.1%) (2.2%)
a) Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily
b) Enoxaparin for at least 5 days, overlapped with and followed by VKA
* p < 0.0026 (non-inferiority to a prespecified hazard ratio of 2.0); hazard ratio: 1.123 (0.749
1.684)
A prespecified pooled analysis of the outcome of the Einstein DVT and PE studies was conducted (see
Table 5).
Table 5: Efficacy and safety results from pooled analysis of phase III Einstein DVT and
Einstein PE
Study population 8,281 patients with an acute symptomatic DVT or PE
Xareltoa) Enoxaparin/VKAb)
Treatment dosage and duration 3, 6 or 12 months 3, 6 or 12 months
N=4,150 N=4,131
86 95
Symptomatic recurrent VTE* (2.1%) (2.3%)
43 38
Symptomatic recurrent PE
(1.0%) (0.9%)
32 45
Symptomatic recurrent DVT
(0.8%) (1.1%)
1 2
Symptomatic PE and DVT
(<0.1%) (<0.1%)
Fatal PE/Death where PE 15 13
cannot be ruled out (0.4%) (0.3%)
Major or clinically relevant non- 388 412
major bleeding (9.4%) (10.0%)
40 72
Major bleeding events
(1.0%) (1.7%)
a) Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily
b) Enoxaparin for at least 5 days, overlapped with and followed by VKA
* p < 0.0001 (non-inferiority to a prespecified hazard ratio of 1.75); hazard ratio: 0.886 (0.661
1.186)
The prespecified net clinical benefit (primary efficacy outcome plus major bleeding events) of the
pooled analysis was reported with a hazard ratio of 0.771 ((95% CI: 0.614 0.967), nominal p value
p= 0.0244).
97
In the Einstein Extension study (see Table 6) rivaroxaban was superior to placebo for the primary and
secondary efficacy outcomes. For the primary safety outcome (major bleeding events) there was a
non-significant numerically higher incidence rate for patients treated with rivaroxaban 20 mg once
daily compared to placebo. The secondary safety outcome (major or clinically relevant non-major
bleeding events) showed higher rates for patients treated with rivaroxaban 20 mg once daily compared
to placebo.
Table 6: Efficacy and safety results from phase III Einstein Extension
1,197 patients continued treatment and prevention
Study population
of recurrent venous thromboembolism
Xareltoa) Placebo
Treatment dosage and duration 6 or 12 months 6 or 12 months
N=602 N=594
8 42
Symptomatic recurrent VTE* (1.3%) (7.1%)
2 13
Symptomatic recurrent PE
(0.3%) (2.2%)
5 31
Symptomatic recurrent DVT
(0.8%) (5.2%)
Fatal PE/Death where PE 1 1
cannot be ruled out (0.2%) (0.2%)
4 0
Major bleeding events
(0.7%) (0.0%)
Clinically relevant non-major 32 7
bleeding (5.4%) (1.2%)
a) Rivaroxaban 20 mg once daily
* p < 0.0001 (superiority), hazard ratio: 0.185 (0.087 - 0.393)
In addition to the phase III EINSTEIN program, a prospective, non-interventional, open-label cohort
study (XALIA) with central outcome adjudication including recurrent VTE, major bleeding and death
has been conducted. 5,142 patients with acute DVT were enrolled to investigate the long-term safety
of rivaroxaban compared with standard-of-care anticoagulation therapy in clinical practice. Rates of
major bleeding, recurrent VTE and all-cause mortality for rivaroxaban were 0.7%, 1.4% and 0.5%,
respectively. There were differences in patient baseline characteristics including age, cancer and renal
impairment. A pre-specified propensity score stratified analysis was used to adjust for measured
baseline differences but residual confounding may, in spite of this, influence the results. Adjusted
hazard ratios comparing rivaroxaban and standard-of-care for major bleeding, recurrent VTE and all-
cause mortality were 0.77 (95% CI 0.40 - 1.50), 0.91 (95% CI 0.54 - 1.54) and 0.51 (95% CI
0.24 - 1.07), respectively.
These results in clinical practice are consistent with the established safety profile in this indication.
Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with
Xarelto in one or more subsets of the paediatric population in the treatment of thromboembolic events.
The European Medicines Agency has waived the obligation to submit the results of studies with
Xarelto in all subsets of the paediatric population in the prevention of thromboembolic events (see
section 4.2 for information on paediatric use).
Absorption
Rivaroxaban is rapidly absorbed with maximum concentrations (Cmax) appearing 2 - 4 hours after
tablet intake.
Oral absorption of rivaroxaban is almost complete and oral bioavailability is high (80 - 100%) for the
2.5 mg and 10 mg tablet dose, irrespective of fasting/fed conditions. Intake with food does not affect
rivaroxaban AUC or Cmax at the 2.5 mg and 10 mg dose.
98
Due to a reduced extent of absorption an oral bioavailability of 66% was determined for the 20 mg
tablet under fasting conditions. When Xarelto 20 mg tablets are taken together with food increases in
mean AUC by 39% were observed when compared to tablet intake under fasting conditions, indicating
almost complete absorption and high oral bioavailability. Xarelto 15 mg and 20 mg are to be taken
with food (see section 4.2).
Rivaroxaban pharmacokinetics are approximately linear up to about 15 mg once daily in fasting state.
Under fed conditions Xarelto 10 mg, 15 mg and 20 mg tablets demonstrated dose-proportionality. At
higher doses rivaroxaban displays dissolution limited absorption with decreased bioavailability and
decreased absorption rate with increased dose.
Variability in rivaroxaban pharmacokinetics is moderate with inter-individual variability (CV%)
ranging from 30% to 40%.
Absorption of rivaroxaban is dependent on the site of its release in the gastrointestinal tract. A 29%
and 56% decrease in AUC and Cmax compared to tablet was reported when rivaroxaban granulate is
released in the proximal small intestine. Exposure is further reduced when rivaroxaban is released in
the distal small intestine, or ascending colon. Therefore, administration of rivaroxaban distal to the
stomach should be avoided since this can result in reduced absorption and related rivaroxaban
exposure.
Bioavailability (AUC and Cmax) was comparable for 20 mg rivaroxaban administered orally as a
crushed tablet mixed in apple puree, or suspended in water and administered via a gastric tube
followed by a liquid meal, compared to a whole tablet. Given the predictable, dose-proportional
pharmacokinetic profile of rivaroxaban, the bioavailability results from this study are likely applicable
to lower rivaroxaban doses.
Distribution
Plasma protein binding in humans is high at approximately 92 % to 95 %, with serum albumin being
the main binding component. The volume of distribution is moderate with Vss being approximately
50 litres.
Special populations
Gender
There were no clinically relevant differences in pharmacokinetics and pharmacodynamics between
male and female patients.
Elderly population
Elderly patients exhibited higher plasma concentrations than younger patients, with mean AUC values
being approximately 1.5 fold higher, mainly due to reduced (apparent) total and renal clearance. No
dose adjustment is necessary.
99
Inter-ethnic differences
No clinically relevant inter-ethnic differences among Caucasian, African-American, Hispanic,
Japanese or Chinese patients were observed regarding rivaroxaban pharmacokinetics and
pharmacodynamics.
Hepatic impairment
Cirrhotic patients with mild hepatic impairment (classified as Child Pugh A) exhibited only minor
changes in rivaroxaban pharmacokinetics (1.2 fold increase in rivaroxaban AUC on average), nearly
comparable to their matched healthy control group. In cirrhotic patients with moderate hepatic
impairment (classified as Child Pugh B), rivaroxaban mean AUC was significantly increased by
2.3 fold compared to healthy volunteers. Unbound AUC was increased 2.6 fold. These patients also
had reduced renal elimination of rivaroxaban, similar to patients with moderate renal impairment.
There are no data in patients with severe hepatic impairment.
The inhibition of factor Xa activity was increased by a factor of 2.6 in patients with moderate hepatic
impairment as compared to healthy volunteers; prolongation of PT was similarly increased by a factor
of 2.1. Patients with moderate hepatic impairment were more sensitive to rivaroxaban resulting in a
steeper PK/PD relationship between concentration and PT.
Xarelto is contraindicated in patients with hepatic disease associated with coagulopathy and clinically
relevant bleeding risk, including cirrhotic patients with Child Pugh B and C (see section 4.3).
Renal impairment
There was an increase in rivaroxaban exposure correlated to decrease in renal function, as assessed via
creatinine clearance measurements. In individuals with mild (creatinine clearance 50 - 80 ml/min),
moderate (creatinine clearance 30 - 49 ml/min) and severe (creatinine clearance 15 - 29 ml/min) renal
impairment, rivaroxaban plasma concentrations (AUC) were increased 1.4, 1.5 and 1.6 fold
respectively. Corresponding increases in pharmacodynamic effects were more pronounced. In
individuals with mild, moderate and severe renal impairment the overall inhibition of factor Xa
activity was increased by a factor of 1.5, 1.9 and 2.0 respectively as compared to healthy volunteers;
prolongation of PT was similarly increased by a factor of 1.3, 2.2 and 2.4 respectively. There are no
data in patients with creatinine clearance < 15 ml/min.
Due to the high plasma protein binding rivaroxaban is not expected to be dialysable.
Use is not recommended in patients with creatinine clearance < 15 ml/min. Xarelto is to be used with
caution in patients with creatinine clearance 15 - 29 ml/min (see section 4.4).
Pharmacokinetic/pharmacodynamic relationship
The pharmacokinetic/pharmacodynamic (PK/PD) relationship between rivaroxaban plasma
concentration and several PD endpoints (factor Xa inhibition, PT, aPTT, Heptest) has been evaluated
after administration of a wide range of doses (5 - 30 mg twice a day). The relationship between
rivaroxaban concentration and factor Xa activity was best described by an Emax model. For PT, the
linear intercept model generally described the data better. Depending on the different PT reagents
used, the slope differed considerably. When Neoplastin PT was used, baseline PT was about 13 s and
the slope was around 3 to 4 s/(100 g/l). The results of the PK/PD analyses in Phase II and III were
consistent with the data established in healthy subjects.
Paediatric population
Safety and efficacy have not been established for children and adolescents up to 18 years.
100
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, single dose toxicity, phototoxicity, genotoxicity, carcinogenic potential and juvenile
toxicity.
Effects observed in repeat-dose toxicity studies were mainly due to the exaggerated pharmacodynamic
activity of rivaroxaban. In rats, increased IgG and IgA plasma levels were seen at clinically relevant
exposure levels.
In rats, no effects on male or female fertility were seen. Animal studies have shown reproductive
toxicity related to the pharmacological mode of action of rivaroxaban (e.g. haemorrhagic
complications). Embryo-foetal toxicity (post-implantation loss, retarded/progressed ossification,
hepatic multiple light coloured spots) and an increased incidence of common malformations as well as
placental changes were observed at clinically relevant plasma concentrations. In the pre- and post-
natal study in rats, reduced viability of the offspring was observed at doses that were toxic to the dams.
6. PHARMACEUTICAL PARTICULARS
Tablet core:
Microcrystalline cellulose
Croscarmellose sodium
Lactose monohydrate
Hypromellose
Sodium laurilsulfate
Magnesium stearate
Film-coat:
Macrogol 3350
Hypromellose
Titanium dioxide (E171)
Iron oxide red (E172)
6.2 Incompatibilities
Not applicable.
3 years
This medicinal product does not require any special storage conditions.
101
7. MARKETING AUTHORISATION HOLDER
Bayer Pharma AG
13342 Berlin
Germany
EU/1/08/472/040
{MM/YYYY}
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu.
102
ANNEX II
103
A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
Bayer Pharma AG
51368 Leverkusen
Germany
The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch.
The marketing authorisation holder shall submit periodic safety update reports for this product in
accordance with the requirements set out in the list of Union reference dates (EURD list) provided for
under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal.
The MAH shall perform the required pharmacovigilance activities and interventions detailed in
the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed
subsequent updates of the RMP.
If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the
same time.
104
Additional risk minimisation measures
The MAH shall provide an educational pack prior to launch, targeting all physicians who are expected
to prescribe/use Xarelto. The educational pack is aimed at increasing awareness about the potential
risk of bleeding during treatment with Xarelto and providing guidance on how to manage that risk.
The physician educational pack should contain:
The Summary of Product Characteristics
Prescriber Guide
Patient Alert Cards [Text included in Annex III]
The MAH must agree the content and format of the Prescriber Guide together with a communication
plan, with the national competent authority in each Member State prior to distribution of the
educational pack in their territory. The Prescriber Guide should contain the following key safety
messages:
Details of populations potentially at higher risk of bleeding
Recommendations for dose reduction in at risk populations
Guidance regarding switching from or to rivaroxaban treatment
The need for intake of the 15 mg and 20 mg tablets with food
Management of overdose situations
The use of coagulation tests and their interpretation
That all patients should be counselled about:
Signs or symptoms of bleeding and when to seek attention from a health care
provider.
Importance of treatment compliance
The need for intake of the 15 mg and 20 mg tablets with food
Necessity to carry the Patient Alert Card that is included in each pack, with them at all
times
The need to inform Health Care Professionals that they are taking Xarelto if they need
to have any surgery or invasive procedure.
The MAH shall also provide a Patient Alert Card in each medication pack, the text of which is
included in Annex III.
The MAH shall complete, within the stated timeframe, the below measures:
105
ANNEX III
106
A. LABELLING
107
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
3. LIST OF EXCIPIENTS
14 film-coated tablets
28 film-coated tablets
56 film-coated tablets
60 film-coated tablets
98 film-coated tablets
168 film-coated tablets
196 film-coated tablets
10 x 1 film-coated tablets
100 x 1 film-coated tablets
30 film-coated tablets
8. EXPIRY DATE
EXP
108
9. SPECIAL STORAGE CONDITIONS
Bayer Pharma AG
13342 Berlin
Germany
Batch
Xarelto 2.5 mg
109
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
3. LIST OF EXCIPIENTS
8. EXPIRY DATE
EXP
110
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Bayer Pharma AG
13342 Berlin
Germany
Batch
Xarelto 2.5 mg
111
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
3. LIST OF EXCIPIENTS
10 x 1 film-coated tablets.
Component of a multipack, cant be sold separately.
8. EXPIRY DATE
EXP
112
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Bayer Pharma AG
13342 Berlin
Germany
Batch
Xarelto 2.5 mg
113
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Bayer (logo)
3. EXPIRY DATE
EXP
4. BATCH NUMBER
Lot
5. OTHER
114
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Bayer (logo)
3. EXPIRY DATE
EXP
4. BATCH NUMBER
Lot
5. OTHER
115
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Bayer (logo)
3. EXPIRY DATE
EXP
4. BATCH NUMBER
Lot
5. OTHER
Mon.
Tue.
Wed.
Thu.
Fri.
Sat.
Sun.
sun as symbol
moon as symbol
116
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
3. LIST OF EXCIPIENTS
5 film-coated tablets
10 film-coated tablets
30 film-coated tablets
10 x 1 film-coated tablets
100 x 1 film-coated tablets
8. EXPIRY DATE
EXP
117
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Bayer Pharma AG
13342 Berlin
Germany
Batch
Xarelto 10 mg
118
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
3. LIST OF EXCIPIENTS
8. EXPIRY DATE
EXP
119
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Bayer Pharma AG
13342 Berlin
Germany
Batch
Xarelto 10 mg
120
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
3. LIST OF EXCIPIENTS
10 x 1 film-coated tablets.
Component of a multipack, cant be sold separately.
8. EXPIRY DATE
EXP
121
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Bayer Pharma AG
13342 Berlin
Germany
Batch
Xarelto 10 mg
122
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER FOR 10 MG
Xarelto 10 mg tablets
rivaroxaban
Bayer (logo)
3. EXPIRY DATE
EXP
4. BATCH NUMBER
Lot
5. OTHER
123
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
3. LIST OF EXCIPIENTS
10 film-coated tablets
14 film-coated tablets
28 film-coated tablets
42 film-coated tablets
98 film-coated tablets
10 x 1 film-coated tablets
100 x 1 film-coated tablets
8. EXPIRY DATE
EXP
124
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Bayer Pharma AG
13342 Berlin
Germany
Batch
Xarelto 15 mg
125
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
3. LIST OF EXCIPIENTS
8. EXPIRY DATE
EXP
126
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Bayer Pharma AG
13342 Berlin
Germany
Batch
Xarelto 15 mg
127
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
3. LIST OF EXCIPIENTS
10 x 1 film-coated tablets.
Component of a multipack, cant be sold separately.
8. EXPIRY DATE
EXP
128
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Bayer Pharma AG
13342 Berlin
Germany
Batch
Xarelto 15 mg
129
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Xarelto 15 mg tablets
rivaroxaban
Bayer (logo)
3. EXPIRY DATE
EXP
4. BATCH NUMBER
Lot
5. OTHER
130
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Xarelto 15 mg tablets
rivaroxaban
Bayer (logo)
3. EXPIRY DATE
EXP
4. BATCH NUMBER
Lot
5. OTHER
Mon.
Tue.
Wed.
Thu.
Fri.
Sat.
Sun.
131
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Xarelto 15 mg tablets
rivaroxaban
Bayer (logo)
3. EXPIRY DATE
EXP
4. BATCH NUMBER
Lot
5. OTHER
132
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
3. LIST OF EXCIPIENTS
8. EXPIRY DATE
EXP
133
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Bayer Pharma AG
13342 Berlin
Germany
Batch
Xarelto 15 mg (only applicable for outer carton, not applicable for bottle label)
134
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
3. LIST OF EXCIPIENTS
10 film-coated tablets
14 film-coated tablets
28 film-coated tablets
98 film-coated tablets
10 x 1 film-coated tablets
100 x 1 film-coated tablets
8. EXPIRY DATE
EXP
135
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Bayer Pharma AG
13342 Berlin
Germany
Batch
Xarelto 20 mg
136
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
3. LIST OF EXCIPIENTS
8. EXPIRY DATE
EXP
137
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Bayer Pharma AG
13342 Berlin
Germany
Batch
Xarelto 20 mg
138
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
3. LIST OF EXCIPIENTS
10 x 1 film-coated tablets.
Component of a multipack, cant be sold separately.
8. EXPIRY DATE
EXP
139
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Bayer Pharma AG
13342 Berlin
Germany
Batch
Xarelto 20 mg
140
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Xarelto 20 mg tablets
rivaroxaban
Bayer (logo)
3. EXPIRY DATE
EXP
4. BATCH NUMBER
Lot
5. OTHER
141
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Xarelto 20 mg tablets
rivaroxaban
Bayer (logo)
3. EXPIRY DATE
EXP
4. BATCH NUMBER
Lot
5. OTHER
Mon.
Tue.
Wed.
Thu.
Fri.
Sat.
Sun.
142
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Xarelto 20 mg tablets
rivaroxaban
Bayer (logo)
3. EXPIRY DATE
EXP
4. BATCH NUMBER
Lot
5. OTHER
143
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
3. LIST OF EXCIPIENTS
8. EXPIRY DATE
EXP
144
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Bayer Pharma AG
13342 Berlin
Germany
Batch
Xarelto 20 mg (only applicable for outer carton, not applicable for bottle label)
145
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Xarelto 15 mg
Xarelto 20 mg
film-coated tablets
rivaroxaban
3. LIST OF EXCIPIENTS
This treatment initiation pack is only for the first 4 weeks of treatment.
DOSE
Day 1 to 21: One 15 mg tablet twice a day (one 15 mg tablet in the morning and one in the evening)
together with food.
From Day 22: One 20 mg tablet once a day (taken at same time each day) together with food.
Day 1 to 21: 15 mg 1 tablet twice a day (one 15 mg tablet in the morning and one in the evening)
together with food.
From Day 22: 20 mg 1 tablet once a day (taken at same time each day) together with food.
146
7. OTHER SPECIAL WARNING(S), IF NECESSARY
8. EXPIRY DATE
EXP
Bayer Pharma AG
13342 Berlin
Germany
Batch
Xarelto 15 mg
Xarelto 20 mg
147
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Xarelto 15 mg
Xarelto 20 mg
film-coated tablets
rivaroxaban
3. LIST OF EXCIPIENTS
This treatment initiation pack is only for the first 4 weeks of treatment.
Day 1 to 21: 15 mg 1 tablet twice a day (one 15 mg tablet in the morning and one in the evening)
together with food.
From Day 22: 20 mg 1 tablet once a day (taken at same time each day) together with food.
Xarelto 15 mg
148
Start of therapy
15 mg
twice a day
Start date
WEEK 1, WEEK 2, WEEK 3
DAY 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
sun as symbol
moon as symbol
Dose change
Xarelto 20 mg
20 mg
once a day
taken at same time each day
Date of dose change
WEEK 4
DAY 22 DAY 23 DAY 24 DAY 25 DAY 26 DAY 27 DAY 28
8. EXPIRY DATE
EXP
Bayer Pharma AG
13342 Berlin
Germany
149
13. BATCH NUMBER
Batch
150
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Xarelto 15 mg tablets
Xarelto 20 mg tablets
rivaroxaban
Bayer (logo)
3. EXPIRY DATE
EXP
4. BATCH NUMBER
Lot
5. OTHER
151
PATIENT ALERT CARD
Xarelto 2.5 mg
Xarelto 15 mg
Xarelto 20 mg
152
coughing up blood, or vomiting blood or material that looks like coffee grounds
153
B. PACKAGE LEAFLET
154
Package leaflet: Information for the user
This medicine is subject to additional monitoring. This will allow quick identification of new
safety information. You can help by reporting any side effects you may get. See the end of section 4
for how to report side effects.
Read all of this leaflet carefully before you start taking this medicine because it contains
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,
even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side
effects not listed in this leaflet. See section 4.
You have been given Xarelto because you have been diagnosed with an acute coronary syndrome (a
group of conditions that includes heart attack and unstable angina, a severe type of chest pain) and
have been shown to have had an increase in certain cardiac blood tests.
Xarelto reduces the risk in adults of having another heart attack or reduces the risk of dying from a
disease related to your heart or your blood vessels.
Xarelto contains the active substance rivaroxaban and belongs to a group of medicines called
antithrombotic agents. It works by blocking a blood clotting factor (factor Xa) and thus reducing the
tendency of the blood to form clots.
Xarelto will not be given to you on its own. Your doctor will also tell you to take either:
acetylsalicylic acid (also known as aspirin) or
acetylsalicylic acid plus clopidogrel or ticlopidine.
155
Do not take Xarelto
- if you are allergic to rivaroxaban or any of the other ingredients of this medicine (listed in
section 6)
- if you are bleeding excessively
- if you have a disease or condition in an organ of the body that increases the risk of serious
bleeding (e.g., stomach ulcer, injury or bleeding in the brain, recent surgery of the brain or eyes)
- if you are taking medicines to prevent blood clotting (e.g. warfarin, dabigatran, apixaban or
heparin), except when changing anticoagulant treatment or while getting heparin through a
venous or arterial line to keep it open
- if you have an acute coronary syndrome and previously had a bleeding or a blood clot in your
brain (stroke)
- if you have a liver disease which leads to an increased risk of bleeding
- if you are pregnant or breast feeding
Do not take Xarelto and tell your doctor if any of these apply to you.
If any of the above apply to you, tell your doctor before you take Xarelto. Your doctor will decide,
if you should be treated with this medicine and if you should be kept under closer observation.
156
Other medicines and Xarelto
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other
medicines, including medicines obtained without a prescription.
- If you are taking:
some medicines for fungal infections (e.g. ketoconazole, itraconazole, voriconazole,
posaconazole), unless they are only applied to the skin
some anti-viral medicines for HIV / AIDS (e.g. ritonavir)
other medicines to reduce blood clotting (e.g. enoxaparin, clopidogrel or vitamin K
antagonists such as warfarin and acenocoumarol)
anti-inflammatory and pain relieving medicines (e.g. naproxen or acetylsalicylic acid)
dronedarone, a medicine to treat abnormal heart beat
If any of the above apply to you, tell your doctor before taking Xarelto, because the effect of
Xarelto may be increased. Your doctor will decide, if you should be treated with this medicine
and if you should be kept under closer observation.
If your doctor thinks that you are at increased risk of developing stomach or bowel ulcers, he
may also use a preventative ulcer treatment.
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist
if you are not sure.
If you have difficulty swallowing the tablet whole, talk to your doctor about other ways to take
Xarelto. The tablet may be crushed and mixed with water or apple puree immediately before you take
it.
If necessary, your doctor may also give you the crushed Xarelto tablet through a stomach tube.
Xarelto will not be given to you on its own. Your doctor will also tell you to take either:
acetylsalicylic acid (also known as aspirin) or
157
acetylsalicylic acid plus clopidogrel or ticlopidine.
Your doctor will tell you how much of these to take (usually between 75 to 100 mg acetylsalicylic acid
daily or a daily dose of 75 to 100 mg acetylsalicylic acid plus a daily dose of either 75 mg clopidogrel
or a standard daily dose of ticlopidine).
Do not stop taking Xarelto without talking to your doctor first. If you stop taking this medicine, it may
increase your risk of having another heart attack or stroke or dying from a disease related to your heart
or your blood vessels.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Like all medicines, Xarelto can cause side effects, although not everybody gets them.
Like other similar medicines (antithrombotic agents), Xarelto may cause bleeding which may
potentially be life threatening. Excessive bleeding may lead to a sudden drop in blood pressure
(shock). In some cases the bleeding may not be obvious.
158
- pain in the limbs
- fever
- reduction in red blood cells which can make the skin pale and cause weakness or breathlessness
- stomach ache, indigestion, feeling or being sick, constipation, diarrhoea
- low blood pressure (symptoms may be feeling dizzy or fainting when standing up)
- decreased general strength and energy (weakness, tiredness), headache, dizziness
- rash, itchy skin
- impaired function of the kidneys (may be seen in tests performed by your doctor)
- blood tests may show an increase in some liver enzymes
Do not use this medicine after the expiry date which is stated on the carton and on each blister after
EXP. The expiry date refers to the last day of that month.
159
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to
throw away medicines you no longer use. These measures will help protect the environment.
Bayer Pharma AG
13342 Berlin
Germany
Manufacturer
Bayer Pharma AG
51368 Leverkusen
Germany
160
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
Detailed information on this medicine is available on the European Medicines Agency website:
http://www.ema.europa.eu.
161
Package leaflet: Information for the user
This medicine is subject to additional monitoring. This will allow quick identification of new
safety information. You can help by reporting any side effects you may get. See the end of section 4
for how to report side effects.
Read all of this leaflet carefully before you start taking this medicine because it contains
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,
even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side
effects not listed in this leaflet. See section 4.
Xarelto contains the active substance rivaroxaban and is used in adults to prevent blood clots in the
veins after a hip or knee replacement operation. Your doctor has prescribed this medicine for you
because after an operation you are at an increased risk of getting blood clots.
Xarelto belongs to a group of medicines called antithrombotic agents. It works by blocking a blood
clotting factor (factor Xa) and thus reducing the tendency of the blood to form clots.
162
Take special care with Xarelto
- if you have an increased risk of bleeding, as could be the case in situations such as:
moderate or severe kidney disease, since your kidney function may affect the amount of
medicine that works in your body
if you are taking other medicines to prevent blood clotting (e.g. warfarin, dabigatran,
apixaban or heparin), when changing anticoagulant treatment or while getting heparin
through a venous or arterial line to keep it open (see section Other medicines and
Xarelto)
bleeding disorders
very high blood pressure, not controlled by medical treatment
diseases of your stomach or bowel that might result in bleeding, e.g. inflammation of the
bowels or stomach, or inflammation of the oesophagus (gullet) e.g. due to
gastroesophageal reflux disease (disease where stomach acid goes upwards into the
oesophagus)
a problem with the blood vessels in the back of your eyes (retinopathy)
a lung disease where your bronchi are widened and filled with pus (bronchiectasis), or
previous bleeding from your lung
If any of the above apply to you, tell your doctor before you take Xarelto. Your doctor will decide,
if you should be treated with this medicine and if you should be kept under closer observation.
If your operation involves a catheter or injection into your spinal column (e.g. for epidural or spinal
anaesthesia or pain reduction):
it is very important to take Xarelto exactly at the times you have been told by your doctor
tell your doctor immediately if you get numbness or weakness of your legs or problems
with your bowel or bladder after the end of anaesthesia, because urgent care is necessary.
If any of the above apply to you, tell your doctor before taking Xarelto, because the effect of
Xarelto may be increased. Your doctor will decide, if you should be treated with this medicine
and if you should be kept under closer observation.
If your doctor thinks that you are at increased risk of developing stomach or bowel ulcers, he
may also use a preventative ulcer treatment.
163
If any of the above apply to you, tell your doctor before taking Xarelto, because the effect of
Xarelto may be reduced. Your doctor will decide, if you should be treated with Xarelto and if
you should be kept under closer observation.
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist
if you are not sure.
If you have difficulty swallowing the tablet whole, talk to your doctor about other ways to take
Xarelto. The tablet may be crushed and mixed with water or apple puree immediately before you take
it.
If necessary, your doctor may also give you the crushed Xarelto tablet through a stomach tube.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
164
4. Possible side effects
Like all medicines, Xarelto can cause side effects, although not everybody gets them.
Like other similar medicines (antithrombotic agents), Xarelto may cause bleeding which may
potentially be life threatening. Excessive bleeding may lead to a sudden drop in blood pressure
(shock). In some cases the bleeding may not be obvious.
165
Not known (frequency cannot be estimated from the available data):
- increased pressure within muscles of the legs or arms after a bleeding, which leads to pain, swelling,
altered sensation, numbness or paralysis (compartment syndrome after a bleeding)
- kidney failure after a severe bleeding
Do not use this medicine after the expiry date which is stated on the carton and on each blister after
EXP. The expiry date refers to the last day of that month.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to
throw away medicines you no longer use. These measures will help protect the environment.
Bayer Pharma AG
13342 Berlin
Germany
166
Manufacturer
Bayer Pharma AG
51368 Leverkusen
Germany
167
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
Detailed information on this medicine is available on the European Medicines Agency website:
http://www.ema.europa.eu.
168
Package leaflet: Information for the user
This medicine is subject to additional monitoring. This will allow quick identification of new
safety information. You can help by reporting any side effects you may get. See the end of section 4
for how to report side effects.
Read all of this leaflet carefully before you start taking this medicine because it contains
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,
even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side
effects not listed in this leaflet. See section 4.
Xarelto contains the active substance rivaroxaban and is used in adults to:
- prevent blood clots in brain (stroke) and other blood vessels in your body if you have a form of
irregular heart rhythm called non-valvular atrial fibrillation.
- treat blood clots in the veins of your legs (deep vein thrombosis) and in the blood vessels of
your lungs (pulmonary embolism), and to prevent blood clots from re-occurring in the blood
vessels of your legs and/or lungs.
Xarelto belongs to a group of medicines called antithrombotic agents. It works by blocking a blood
clotting factor (factor Xa) and thus reducing the tendency of the blood to form clots.
169
Warnings and precautions
Talk to your doctor or pharmacist before taking Xarelto.
If any of the above apply to you, tell your doctor before you take Xarelto. Your doctor will decide,
if you should be treated with this medicine and if you should be kept under closer observation.
If any of the above apply to you, tell your doctor before taking Xarelto, because the effect of
Xarelto may be increased. Your doctor will decide, if you should be treated with this medicine
and if you should be kept under closer observation.
170
If your doctor thinks that you are at increased risk of developing stomach or bowel ulcers, he
may also use a preventative ulcer treatment.
If any of the above apply to you, tell your doctor before taking Xarelto, because the effect of
Xarelto may be reduced. Your doctor will decide, if you should be treated with Xarelto and if
you should be kept under closer observation.
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist
if you are not sure.
- To treat blood clots in the veins of your legs and blood clots in the blood vessels of your lungs,
and for preventing blood clots from re-occurring
The recommended dose is one 15 mg tablet twice a day for the first 3 weeks. For treatment after
3 weeks, the recommended dose is one 20 mg tablet once a day.
If you have kidney problems, your doctor may decide to reduce the dose for the treatment after
3 weeks to one 15 mg tablet once a day if the risk for bleeding is greater than the risk for having
another blood clot.
If you have difficulty swallowing the tablet whole, talk to your doctor about other ways to take
Xarelto. The tablet may be crushed and mixed with water or apple puree immediately before you take
it. This mixture should be immediately followed by food.
If necessary, your doctor may also give you the crushed Xarelto tablet through a stomach tube.
171
To prevent blood clots in the brain (stroke) and other blood vessels in your body:
If your heart beat needs to be restored to normal by a procedure called cardioversion, take Xarelto at
the times your doctor tells you.
- If you are taking one 15 mg tablet twice a day and have missed a dose, take it as soon as you
remember. Do not take more than two 15 mg tablets in a single day. If you forget to take a dose
you can take two 15 mg tablets at the same time to get a total of two tablets (30 mg) on one day.
On the following day you should carry on taking one 15 mg tablet twice a day.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Like all medicines, Xarelto can cause side effects, although not everybody gets them.
Like other similar medicines (antithrombotic agents), Xarelto may cause bleeding which may
potentially be life threatening. Excessive bleeding may lead to a sudden drop in blood pressure
(shock). In some cases the bleeding may not be obvious.
172
- low blood pressure (symptoms may be feeling dizzy or fainting when standing up)
- decreased general strength and energy (weakness, tiredness), headache, dizziness
- rash, itchy skin
- impaired function of the kidneys (may be seen in tests performed by your doctor)
- blood tests may show an increase in some liver enzymes
Do not use this medicine after the expiry date which is stated on the carton and on each blister after
EXP.
The expiry date refers to the last day of that month.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to
throw away medicines you no longer use. These measures will help protect the environment.
173
6. Contents of the pack and other information
Xarelto 20 mg film-coated tablets are brown-red, round, biconvex and marked with the BAYER-cross
on one side and 20 and a triangle on the other.
They come in blisters in cartons of 10, 14, 28 or 98 film-coated tablets or unit dose blisters in cartons
of 10 x 1 or 100 x 1 or in multipacks comprising 10 cartons, each containing 10 x 1 film-coated tablets
or in bottles of 100 film-coated tablets.
Bayer Pharma AG
13342 Berlin
Germany
Manufacturer
Bayer Pharma AG
51368 Leverkusen
Germany
174
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
Detailed information on this medicine is available on the European Medicines Agency website:
http://www.ema.europa.eu.
175
Package leaflet: Information for the user
This medicine is subject to additional monitoring. This will allow quick identification of new
safety information. You can help by reporting any side effects you may get. See the end of section 4
for how to report side effects.
Read all of this leaflet carefully before you start taking this medicine because it contains
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,
even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side
effects not listed in this leaflet. See section 4.
Xarelto contains the active substance rivaroxaban and is used in adults to:
- treat blood clots in the veins of your legs (deep vein thrombosis) and in the blood vessels of
your lungs (pulmonary embolism), and to prevent blood clots from re-occurring in the blood
vessels of your legs and/or lungs.
Xarelto belongs to a group of medicines called antithrombotic agents. It works by blocking a blood
clotting factor (factor Xa) and thus reducing the tendency of the blood to form clots.
176
Warnings and precautions
Talk to your doctor or pharmacist before taking Xarelto.
If any of the above apply to you, tell your doctor before you take Xarelto. Your doctor will decide,
if you should be treated with this medicine and if you should be kept under closer observation.
If any of the above apply to you, tell your doctor before taking Xarelto, because the effect of
Xarelto may be increased. Your doctor will decide, if you should be treated with this medicine
and if you should be kept under closer observation.
177
If your doctor thinks that you are at increased risk of developing stomach or bowel ulcers, he
may also use a preventative ulcer treatment.
If any of the above apply to you, tell your doctor before taking Xarelto, because the effect of
Xarelto may be reduced. Your doctor will decide, if you should be treated with Xarelto and if
you should be kept under closer observation.
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist
if you are not sure.
If you have difficulty swallowing the tablet whole, talk to your doctor about other ways to take
Xarelto. The tablet may be crushed and mixed with water or apple puree immediately before you take
it. This mixture should be immediately followed by food.
If necessary, your doctor may also give you the crushed Xarelto tablet through a stomach tube.
178
If you forget to take Xarelto
- If you are taking one 15 mg tablet twice a day and have missed a dose, take it as soon as you
remember. Do not take more than two 15 mg tablets in a single day. If you forget to take a dose
you can take two 15 mg tablets at the same time to get a total of two tablets (30 mg) on one day.
On the following day you should carry on taking one 15 mg tablet twice a day.
- If you are taking one 20 mg tablet once a day and have missed a dose, take it as soon as you
remember. Do not take more than one tablet in a single day to make up for a forgotten dose.
Take the next tablet on the following day and then carry on taking one tablet once a day.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Like all medicines, Xarelto can cause side effects, although not everybody gets them.
Like other similar medicines (antithrombotic agents), Xarelto may cause bleeding which may
potentially be life threatening. Excessive bleeding may lead to a sudden drop in blood pressure
(shock). In some cases the bleeding may not be obvious.
179
Uncommon (may affect up to 1 in 100 people):
- bleeding into the brain or inside the skull
- bleeding into a joint causing pain and swelling
- fainting
- feeling unwell
- dry mouth
- faster heartbeat
- allergic reactions, including allergic skin reactions
- hives
- impaired function of the liver (may be seen in tests performed by your doctor)
- blood tests may show an increase in bilirubin, some pancreatic or liver enzymes or in the number of
platelets
Do not use this medicine after the expiry date which is stated on the carton and on each blister after
EXP.
The expiry date refers to the last day of that month.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to
throw away medicines you no longer use. These measures will help protect the environment.
180
6. Contents of the pack and other information
Bayer Pharma AG
13342 Berlin
Germany
Manufacturer
Bayer Pharma AG
51368 Leverkusen
Germany
181
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
Detailed information on this medicine is available on the European Medicines Agency website:
http://www.ema.europa.eu.
182